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1
Hawkins, Gregory A., David J. Friedman, Lingyi Lu, David R. McWilliams, Jeff W. Chou, Satria Sajuthi, Jasmin Divers, et al. "Re-Sequencing of the APOL1-APOL4 and MYH9 Gene Regions in African Americans Does Not Identify Additional Risks for CKD Progression." American Journal of Nephrology 42, no. 2 (2015): 99–106. http://dx.doi.org/10.1159/000439448.
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Background: In African Americans (AAs), APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in an autosomal recessive pattern. Additional risk and protective genetic variants may be present near the APOL1 loci, since earlier age ESKD is observed in some AAs with one APOL1 renal-risk variant, and because the adjacent gene MYH9 is associated with nephropathy in populations lacking G1 and G2 variants. Methods: Re-sequencing was performed across a ∼275 kb region encompassing the APOL1-APOL4 and MYH9 genes in 154 AA cases with non-diabetic ESKD and 38 controls without nephropathy who were heterozygous for a single APOL1 G1 or G2 risk variant. Results: Sequencing identified 3,246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions. No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1,571 AA ESKD cases and 1,334 controls. After adjusting for APOL1 G1 and G2 risk effects, these variations were not significantly associated with ESKD. In subjects with <2 APOL1 G1 and/or G2 alleles (849 cases; 1,139 controls), the APOL3 null variant was nominally associated with ESKD (recessive model, OR 1.81; p = 0.026); however, analysis in 807 AA cases and 634 controls from the Family Investigation of Nephropathy and Diabetes did not replicate this association. Conclusion: Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles.
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Scales, Suzie J., Nidhi Gupta, Ann M. De Mazière, George Posthuma, Cecilia P. Chiu, Andrew A. Pierce, Kathy Hötzel, et al. "Apolipoprotein L1-Specific Antibodies Detect Endogenous APOL1 inside the Endoplasmic Reticulum and on the Plasma Membrane of Podocytes." Journal of the American Society of Nephrology 31, no. 9 (August 6, 2020): 2044–64. http://dx.doi.org/10.1681/asn.2019080829.
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BackgroundAPOL1 is found in human kidney podocytes and endothelia. Variants G1 and G2 of the APOL1 gene account for the high frequency of nondiabetic CKD among African Americans. Proposed mechanisms of kidney podocyte cytotoxicity resulting from APOL1 variant overexpression implicate different subcellular compartments. It is unclear where endogenous podocyte APOL1 resides, because previous immunolocalization studies utilized overexpressed protein or commercially available antibodies that crossreact with APOL2. This study describes and distinguishes the locations of both APOLs.MethodsImmunohistochemistry, confocal and immunoelectron microscopy, and podocyte fractionation localized endogenous and transfected APOL1 using a large panel of novel APOL1-specific mouse and rabbit monoclonal antibodies.ResultsBoth endogenous podocyte and transfected APOL1 isoforms vA and vB1 (and a little of isoform vC) localize to the luminal face of the endoplasmic reticulum (ER) and to the cell surface, but not to mitochondria, endosomes, or lipid droplets. In contrast, APOL2, isoform vB3, and most vC of APOL1 localize to the cytoplasmic face of the ER and are consequently absent from the cell surface. APOL1 knockout podocytes do not stain for APOL1, attesting to the APOL1-specificity of the antibodies. Stable re-transfection of knockout podocytes with inducible APOL1-G0, -G1, and -G2 showed no differences in localization among variants.ConclusionsAPOL1 is found in the ER and plasma membrane, consistent with either the ER stress or surface cation channel models of APOL1-mediated cytotoxicity. The surface localization of APOL1 variants potentially opens new therapeutic targeting avenues.
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Chen, Teresa K., Aditya L. Surapaneni, Dan E. Arking, Christie M. Ballantyne, Eric Boerwinkle, Jingsha Chen, Josef Coresh, et al. "APOL1 Kidney Risk Variants and Proteomics." Clinical Journal of the American Society of Nephrology 17, no. 5 (April 26, 2022): 684–92. http://dx.doi.org/10.2215/cjn.14701121.
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Background and objectivesThe APOL1 risk variants (G1 and G2) are associated with kidney disease among Black adults, but the clinical presentation is heterogeneous. In mouse models and cell systems, increased gene expression of G1 and G2 confers cytotoxicity. How APOL1 risk variants relate to the circulating proteome warrants further investigation.Design, setting, participants, & measurementsAmong 461 African American Study of Kidney Disease and Hypertension (AASK) participants (mean age: 54 years; 41% women; mean GFR: 46 ml/min per 1.73 m2), we evaluated associations of APOL1 risk variants with 6790 serum proteins (measured via SOMAscan) using linear regression models. Covariates included age, sex, percentage of European ancestry, and protein principal components 1–5. Associated proteins were then evaluated as mediators of APOL1-associated risk for kidney failure. Findings were replicated among 875 Atherosclerosis Risk in Communities (ARIC) study Black participants (mean age: 75 years; 66% women; mean eGFR: 67 ml/min per 1.73 m2).ResultsIn the AASK study, having two (versus zero or one) APOL1 risk alleles was associated with lower serum levels of APOL1 (P=3.11E-13; P=3.12E-06 [two aptamers]), APOL2 (P=1.45E-10), CLSTN2 (P=2.66E-06), MMP-2 (P=2.96E-06), SPOCK2 (P=2.57E-05), and TIMP-2 (P=2.98E-05) proteins. In the ARIC study, APOL1 risk alleles were associated with APOL1 (P=1.28E-11); MMP-2 (P=0.004) and TIMP-2 (P=0.007) were associated only in an additive model, and APOL2 was not available. APOL1 high-risk status was associated with a 1.6-fold greater risk of kidney failure in the AASK study; none of the identified proteins mediated this association. APOL1 protein levels were not associated with kidney failure in either cohort.ConclusionsAPOL1 risk variants were strongly associated with lower circulating levels of APOL1 and other proteins, but none mediated the APOL1-associated risk for kidney failure. APOL1 protein level was also not associated with kidney failure.
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Arunmanee, Wanatchaporn, Richard K. Heenan, and Jeremy H. Lakey. "Determining the amphipol distribution within membrane-protein fibre samples using small-angle neutron scattering." Acta Crystallographica Section D Structural Biology 74, no. 12 (November 30, 2018): 1192–99. http://dx.doi.org/10.1107/s205979831800476x.
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Detergent micelles can solubilize membrane proteins, but there is always a need for a pool of free detergent at the critical micellar concentration to maintain the micelle–monomer equilibrium. Amphipol polymeric surfactants (APols) have been developed to replace conventional detergents in membrane-protein studies, but the role of free amphipol is unclear. It has previously been shown that the removal of free APol causes monodisperse outer membrane protein F (OmpF) to form long filaments. However, any remaining APol could not be resolved using electron microscopy. Here, small-angle neutron scattering with isotope contrast matching was used to separately determine the distributions of membrane protein and amphipol in a mixed sample. The data showed that after existing free amphipol had been removed from monodisperse complexes, a new equilibrium was established between protein–amphipol filaments and a pool of newly liberated free amphipol. The filaments consisted of OmpF proteins surrounded by a belt of Apol, whilst free oblate spheroid micelles of Apol were also present. No indications of long-range order were observed, suggesting a lack of defined structure in the filaments.
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Anderson, Blair R., Erica E. Davis, Marilyn J. Telen, and Allison E. Ashley-Koch. "In Vivo Modeling Of Genetic Mechanisms Associated With Sickle Cell Disease Nephropathy." Blood 122, no. 21 (November 15, 2013): 2224. http://dx.doi.org/10.1182/blood.v122.21.2224.2224.
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Abstract End-organ damage in patients with sickle cell disease (SCD) has become an emergent clinical priority over recent decades due to the increased lifespan of affected individuals. Renal failure (ESRD), which occurs in 4-12% of SCD patients and is strongly associated with early mortality, has become a particular concern. The detection of SCD nephropathy (SCDN) relies on relatively late markers of the disease process, namely proteinuria and reduced glomerular filtration rate (GFR). Therefore, at-risk SCD patients cannot be identified prior to end-organ damage. A genomic region on human chromosome 22 containing two genes, MYH9 and APOL1, has been associated with non-SCD nephropathy, although the primary gene responsible has remained elusive due to strong linkage disequilibrium in this region. Our group demonstrated that both MYH9 and APOL1 are strong, independent genetic predictors of risk for proteinuria in SCD and interact to affect GFR (Ashley-Koch et al., 2011). We have now used zebrafish as a model to study the contribution of each gene (myh9 and apol1) to kidney function and filtration. To test independent effects of the knockdown of myh9 or apol1, we injected morpholino (MO) antisense oligonucleotides in wild-type zebrafish embryos; this resulted in generalized edema (64% [myh9-MO] and 58% [apol1-MO], both significantly different compared to 3% of control embryos) and reduced glomerular filtration (as measured by quantitative dextran clearance; myh9-MO p=0.047 and apol1-MO p=0.042 when compared to control embryos) for both gene suppression models. Each morphant phenotype was rescued significantly by co-injection of each respective wild type human MYH9 (p=0.001) and APOL1 (p=0.043) mRNA. Importantly, co-injection of human mRNA corresponding to other APOL gene family members did not significantly rescue the observed apol1-MO phenotype, suggesting that apol1 is indeed the functional ortholog to the human gene. Next, we investigated the possibility of a genetic interaction between MYH9 and APOL1 by co-suppression of each of the zebrafish orthologous genes. We observed no additive or synergistic effects due to the co-suppression. Instead, the double morphants were indistinguishable from the myh9 morpholino alone, and neither single morpholino could be rescued by the human mRNA of the other gene. These data suggest that MYH9 and APOL1 may function independently but converge on the same biological process to affect risk of SCDN. In addition to evaluating the effects of candidate gene suppression in wild-type models, we have begun to utilize anemic zebrafish models described previously (Shah et al., 2012). Our preliminary work suggests that the myh9 knockdown phenotype is exacerbated under anemic stress. Ongoing efforts are aimed at identifying novel genetic contributions to SCDN through genome-wide association analysis and exome sequencing of extreme phenotypes in SCD patients, with functional evaluation of putative genetic candidates in our zebrafish model. By offering new insights into the contribution of genes that regulate renal function, these results further our understanding of the pathogenesis of SCDN and may provide genetic markers for the identification of at-risk SCD patients prior to the onset of kidney dysfunction. Disclosures: No relevant conflicts of interest to declare.
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Wang, Zhixing, and Fan Wang. "Identification of Ten-Gene Related to Lipid Metabolism for Predicting Overall Survival of Breast Invasive Carcinoma." Contrast Media & Molecular Imaging 2022 (July 11, 2022): 1–16. http://dx.doi.org/10.1155/2022/8348780.
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Background. Predicting the risk of poor prognosis of breast cancer is crucial to treating breast cancer. This study investigated the prognostic assessment of 10 lipid metabolism-related genes constructed as breast cancer models based on this study. Methods. The TCGA database was used to obtain clinical information and expression data of breast cancer patients, and GSEA analysis and univariate and multivariate Cox proportional risk regression models were performed to identify lipid metabolism genes closely associated with overall survival (OS) of breast cancer patients and to construct a prognostic risk score model based on lipid metabolism gene markers. The Kaplan–Meier method was used to analyze the survival status of patients with high and low-risk scores, and ROC curves assessed the accuracy of this risk score. Finally, the relationship between this risk score and clinicopathological characteristics of BRCA was analyzed in a stratified manner, and the validity of this risk score as an independent prognostic factor was determined using univariate and multivariate Cox regression analyses. Results. One hundred and forty-four differentially expressed lipid metabolism-related genes were identified in cancer and paracancerous tissues in BRCA, 21 of which were associated with overall survival (OS) in BRCA P < 0.05 . Univariate and multivariate Cox analyses revealed that age, grade, and risk score were independent prognostic factors for BRCA. Multivariate Cox regression analysis further identified APOL4, NR1H3, SLC25A5, APOL3, OSBPL1A, DYNLT1, IMMT, MAP2K6, ZDHHC8, and RAB2A lipid metabolism-related genes as independent prognostic markers for BRCA. A prognostic risk score model was developed by labeling lipid metabolism genes with these 10 genes, and patients with BRCA with high-risk scores in the model sample had significantly worse OS than those with low-risk P < 0.01 . The ROC curve area (AUC) of this risk score model was 0.712. Conclusion. By mining the TCGA database, we identified 10 lipid metabolism-related genes APOL4, NR1H3, SLC25A5, APOL3, OSBPL1A, DYNLT1, IMMT, MAP2K6, ZDHHC8, and RAB2A, which are closely related to the prognosis of BRCA patients, and constructed a prognostic risk scoring system based on 10 lipid metabolism genes tags.
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Uzureau, Sophie, Laurence Lecordier, Pierrick Uzureau, Dorle Hennig, Jonas H. Graversen, Fabrice Homblé, Pepe Ekulu Mfutu, et al. "APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin." Cell Reports 30, no. 11 (March 2020): 3821–36. http://dx.doi.org/10.1016/j.celrep.2020.02.064.
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Heneghan, J. F., D. H. Vandorpe, B. E. Shmukler, J. A. Giovinazzo, J. Raper, D. J. Friedman, M. R. Pollak, and S. L. Alper. "BH3 domain-independent apolipoprotein L1 toxicity rescued by BCL2 prosurvival proteins." American Journal of Physiology-Cell Physiology 309, no. 5 (September 1, 2015): C332—C347. http://dx.doi.org/10.1152/ajpcell.00142.2015.
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The potent trypanolytic properties of human apolipoprotein L1 (APOL1) can be neutralized by the trypanosome variant surface antigen gene product known as serum resistance-associated protein. However, two common APOL1 haplotypes present uniquely in individuals of West African ancestry each encode APOL1 variants resistant to serum resistance-associated protein, and each confers substantial resistance to human African sleeping sickness. In contrast to the dominantly inherited anti-trypanosomal activity of APOL1, recessive inheritance of these two trypanoprotective APOL1 alleles predisposes to kidney disease. Proposed mechanisms of APOL1 toxicity have included BH3 domain-dependent autophagy and/or ion channel activity. We probed these potential mechanisms by expressing APOL1 in Xenopus laevis oocytes. APOL1 expression in oocytes increased ion permeability and caused profound morphological deterioration (toxicity). Coexpression of BCL2 family members rescued APOL1-associated oocyte toxicity in the order MCL1 ∼ BCLW > BCLXL ∼ BCL2A1 ≫ BCL2. Deletion of nine nominal core BH3 domain residues abolished APOL1-associated toxicity, but missense substitution of the same residues abolished neither oocyte toxicity nor its rescue by coexpressed MCL1. The APOL1 BH3 domain was similarly dispensable for the ability of APOL1 to rescue intact mice from lethal trypanosome challenge. Replacement of most extracellular Na+ by K+ also reduced APOL1-associated oocyte toxicity, allowing demonstration of APOL1-associated increases in Ca2+ and Cl− fluxes and oocyte ion currents, which were similarly reduced by MCL1 coexpression. Thus APOL1 toxicity in Xenopus oocytes is BH3-independent, but can nonetheless be rescued by some BCL2 family proteins.
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Blessing, Natalya A., Zhenzhen Wu, Sethu M. Madhavan, Jonathan W. Choy, Michelle Chen, Myung K. Shin, Maarten Hoek, John R. Sedor, John F. O’Toole, and Leslie A. Bruggeman. "Lack of APOL1 in proximal tubules of normal human kidneys and proteinuric APOL1 transgenic mouse kidneys." PLOS ONE 16, no. 6 (June 17, 2021): e0253197. http://dx.doi.org/10.1371/journal.pone.0253197.
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The mechanism of pathogenesis associated with APOL1 polymorphisms and risk for non-diabetic chronic kidney disease (CKD) is not fully understood. Prior studies have minimized a causal role for the circulating APOL1 protein, thus efforts to understand kidney pathogenesis have focused on APOL1 expressed in renal cells. Of the kidney cells reported to express APOL1, the proximal tubule expression patterns are inconsistent in published reports, and whether APOL1 is synthesized by the proximal tubule or possibly APOL1 protein in the blood is filtered and reabsorbed by the proximal tubule remains unclear. Using both protein and mRNA in situ methods, the kidney expression pattern of APOL1 was examined in normal human and APOL1 bacterial artificial chromosome transgenic mice with and without proteinuria. APOL1 protein and mRNA was detected in podocytes and endothelial cells, but not in tubular epithelia. In the setting of proteinuria, plasma APOL1 protein did not appear to be filtered or reabsorbed by the proximal tubule. A side-by-side examination of commercial antibodies used in prior studies suggest the original reports of APOL1 in proximal tubules likely reflects antibody non-specificity. As such, APOL1 expression in podocytes and endothelia should remain the focus for mechanistic studies in the APOL1-mediated kidney diseases.
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Pratt, Cindy C., and Paul M. M. Weers. "Lipopolysaccharide binding of an exchangeable apolipoprotein, apolipophorin III, from Galleria mellonella." Biological Chemistry 385, no. 11 (November 1, 2004): 1113–19. http://dx.doi.org/10.1515/bc.2004.145.
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AbstractA new role of apolipophorin III (apoLp-III) as an immune activator has emerged recently. To gain insight into this novel function, the interaction of apoLp-III with lipopoly-saccharide (LPS) was investigated. ApoLp-III fromGalleria mellonellawas incubated with LPS fromEscherichia coliO55:B5, and analyzed by non-denaturing polyacrylamide gel electrophoresis (PAGE). Protein staining showed that apoLp-III mobility was significantly reduced. In addition, silver and LPS fluorescent staining demonstrated that LPS mobility was increased upon incubation with apoLp-III. This result suggests association of apoLp-III with LPS. Sodium dodecyl sulfate (SDS) PAGE analysis showed decreased apoLp-III mobility upon LPS addition, indicative of LPS apoLp-III interaction in the presence of SDS. The unique tyrosine residue that resides in apoLp-III was used to provide additional evidence for LPS binding interaction. In the absence of LPS, apoLp-III tyrosine fluorescence was relatively low. However, LPS addition resulted in a progressive increase in the fluorescence intensity, indicating tertiary rearrangement in the environment of tyrosine 142 upon LPS interaction. Other well-characterized apoLp-IIIs were also examined for LPS binding.Manduca sexta,Bombyx moriandLocusta migratoriaapoLp-III were all able to interact with LPS. The ability of apoLp-III to form complexes with LPS supports the proposed role of apoLp-III in innate immunity.
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Gordon, Elisa J., Daniela Amórtegui, Isaac Blancas, Catherine Wicklund, John Friedewald, and Richard R. Sharp. "A Focus Group Study on African American Living Donors’ Treatment Preferences, Sociocultural Factors, and Health Beliefs About Apolipoprotein L1 Genetic Testing." Progress in Transplantation 29, no. 3 (May 30, 2019): 239–47. http://dx.doi.org/10.1177/1526924819854485.
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Introduction: Because apolipoprotein L1 ( APOL1) risk variants may contribute to live donors’ kidney failure postdonation, professional guidelines suggest informing potential donors with African ancestry about the availability of APOL1 genotyping. This study assessed African American (AA) donors’ perceptions of APOL1 genetic testing and how APOL1 may affect ethnic identity. Methods/Approach: Four focus groups were conducted with AA donors about their decision-making for and perceptions of APOL1 genetic testing and donation to inform a new culturally targeted educational brochure on APOL1 genetic testing. Qualitative data were analyzed by thematic analysis. Findings: Seventeen donors participated (47% participation rate). Four major themes emerged. (1) In hypothetical scenarios, most participants would have undergone APOL1 testing during donor evaluation to make a more informed decision, but many would have still donated. (2) Participants desired information about how having 2 APOL1 risk variants affects the donor’s and the recipient’s health. (3) Participants referred to diversity of genetic ancestry and cultural constructions of racial/ethnic identity to question the population at risk for APOL1 risk variants and recommended that all potential donors undergo genetic testing and receive education about APOL1. (4) Participants worried that out-of-pocket costs would deter APOL1 testing and that APOL1 could become a preexisting condition and discriminate against AAs. Discussion: Our findings suggest that AA donors desire APOL1 testing to foster informed consent. Transplant clinicians should be aware of these responses to APOL1 testing and be sensitive to historical issues of distrust and discrimination.
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Tzukerman, Maty, Yeela Shamai, Ifat Abramovich, Eyal Gottlieb, Sara Selig, and Karl Skorecki. "Comparative Analysis of the APOL1 Variants in the Genetic Landscape of Renal Carcinoma Cells." Cancers 14, no. 3 (January 30, 2022): 733. http://dx.doi.org/10.3390/cancers14030733.
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Although the relative risk of renal cell carcinoma associated with chronic kidney injury is particularly high among sub-Saharan African ancestry populations, it is unclear yet whether the APOL1 gene risk variants (RV) for kidney disease additionally elevate this risk. APOL1 G1 and G2 RV contribute to increased risk for kidney disease in black populations, although the disease mechanism has still not been fully deciphered. While high expression levels of all three APOL1 allelic variants, G0 (the wild type allele), G1, and G2 are injurious to normal human cells, renal carcinoma cells (RCC) naturally tolerate inherent high expression levels of APOL1. We utilized CRISPR/Cas9 gene editing to generate isogenic RCC clones expressing APOL1 G1 or G2 risk variants on a similar genetic background, thus enabling a reliable comparison between the phenotypes elicited in RCC by each of the APOL1 variants. Here, we demonstrate that knocking in the G1 or G2 APOL1 alleles, or complete elimination of APOL1 expression, has major effects on proliferation capacity, mitochondrial morphology, cell metabolism, autophagy levels, and the tumorigenic potential of RCC cells. The most striking effect of the APOL1 RV effect was demonstrated in vivo by the complete abolishment of tumor growth in immunodeficient mice. Our findings suggest that, in contrast to the WT APOL1 variant, APOL1 RV are toxic for RCC cells and may act to suppress cancer cell growth. We conclude that the inherent expression of non-risk APOL1 G0 is required for RCC tumorigenicity. RCC cancer cells can hardly tolerate increased APOL1 risk variants expression levels as opposed to APOL1 G0.
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Andrews, Michael, Teruhiko Yoshida, Clark M. Henderson, Hannah Pflaum, Ayako McGregor, Joshua A. Lieberman, Ian H. de Boer, et al. "Variant APOL1 protein in plasma associates with larger particles in humans and mouse models of kidney injury." PLOS ONE 17, no. 10 (October 24, 2022): e0276649. http://dx.doi.org/10.1371/journal.pone.0276649.
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Background Genetic variants in apolipoprotein L1 (APOL1), a protein that protects humans from infection with African trypanosomes, explain a substantial proportion of the excess risk of chronic kidney disease affecting individuals with sub-Saharan ancestry. The mechanisms by which risk variants damage kidney cells remain incompletely understood. In preclinical models, APOL1 expressed in podocytes can lead to significant kidney injury. In humans, studies in kidney transplant suggest that the effects of APOL1 variants are predominantly driven by donor genotype. Less attention has been paid to a possible role for circulating APOL1 in kidney injury. Methods Using liquid chromatography-tandem mass spectrometry, the concentrations of APOL1 were measured in plasma and urine from participants in the Seattle Kidney Study. Asymmetric flow field-flow fractionation was used to evaluate the size of APOL1-containing lipoprotein particles in plasma. Transgenic mice that express wild-type or risk variant APOL1 from an albumin promoter were treated to cause kidney injury and evaluated for renal disease and pathology. Results In human participants, urine concentrations of APOL1 were correlated with plasma concentrations and reduced kidney function. Risk variant APOL1 was enriched in larger particles. In mice, circulating risk variant APOL1-G1 promoted kidney damage and reduced podocyte density without renal expression of APOL1. Conclusions These results suggest that plasma APOL1 is dynamic and contributes to the progression of kidney disease in humans, which may have implications for treatment of APOL1-associated kidney disease and for kidney transplantation.
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Gupta, Nidhi, Xinhua Wang, Xiaohui Wen, Paul Moran, Maciej Paluch, Philip E. Hass, Amy Heidersbach, et al. "Domain-Specific Antibodies Reveal Differences in the Membrane Topologies of Apolipoprotein L1 in Serum and Podocytes." Journal of the American Society of Nephrology 31, no. 9 (August 6, 2020): 2065–82. http://dx.doi.org/10.1681/asn.2019080830.
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BackgroundCirculating APOL1 lyses trypanosomes, protecting against human sleeping sickness. Two common African gene variants of APOL1, G1 and G2, protect against infection by species of trypanosomes that resist wild-type APOL1. At the same time, the protection predisposes humans to CKD, an elegant example of balanced polymorphism. However, the exact mechanism of APOL1-mediated podocyte damage is not clear, including APOL1's subcellular localization, topology, and whether the damage is related to trypanolysis.MethodsAPOL1 topology in serum (HDL particles) and in kidney podocytes was mapped with flow cytometry, immunoprecipitation, and trypanolysis assays that tracked 170 APOL1 domain-specific monoclonal antibodies. APOL1 knockout podocytes confirmed antibody specificity.ResultsAPOL1 localizes to the surface of podocytes, with most of the pore-forming domain (PFD) and C terminus of the Serum Resistance Associated-interacting domain (SRA-ID), but not the membrane-addressing domain (MAD), being exposed. In contrast, differential trypanolytic blocking activity reveals that the MAD is exposed in serum APOL1, with less of the PFD accessible. Low pH did not detectably alter the gross topology of APOL1, as determined by antibody accessibility, in serum or on podocytes.ConclusionsOur antibodies highlighted different conformations of native APOL1 topology in serum (HDL particles) and at the podocyte surface. Our findings support the surface ion channel model for APOL1 risk variant–mediated podocyte injury, as well as providing domain accessibility information for designing APOL1-targeted therapeutics.
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Gordon, Elisa J., Catherine Wicklund, Jungwha Lee, Richard R. Sharp, and John Friedewald. "A National Survey of Transplant Surgeons and Nephrologists on Implementing Apolipoprotein L1 (APOL1) Genetic Testing Into Clinical Practice." Progress in Transplantation 29, no. 1 (December 13, 2018): 26–35. http://dx.doi.org/10.1177/1526924818817048.
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Introduction: There is debate over whether Apolipoprotein L1 (APOL1) gene risk variants contribute to African American (AA) live donors’ (LD) increased risk of kidney failure. Little is known about factors influencing physicians’ integration of APOL1 genetic testing of AA LDs into donor evaluation. Design: We conducted a cross-sectional survey, informed by Roger’s Diffusion of Innovations theory, among nephrology and surgeon members of the American Society of Nephrology, American Society of Transplantation, and American Society of Transplant Surgeons about their practices of and attitudes about APOL1 genetic testing of AA potential LDs. Descriptive statistics and bivariate analyses were performed. Results: Of 383 completed surveys, most physicians believed that APOL1 testing can help AA LDs make more informed donation decisions (87%), and the addition of APOL1 testing offers better clinical information about AA LD’s eligibility for donation than existing evaluation approaches (74%). Among respondents who evaluate LDs (n = 345), 63% would definitely or probably begin or continue using APOL1 testing in the next year, however, few use APOL1 testing routinely (4%) or on a case-by-case basis (14%). Most did not know the right clinical scenario to order APOL1 testing (59%), but would use educational materials to counsel AA LDs about APOL1 testing (97%). Discussion: Although physicians were highly supportive of APOL1 genetic testing for AA LDs, few physicians use APOL1 testing. As more physicians intend to use APOL1 testing, an ethical framework and clinical decision support are needed presently to assist clinicians in clarifying the proper indication of APOL1 genetic testing.
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Chun, Justin, Jia-Yue Zhang, Maris S. Wilkins, Balajikarthick Subramanian, Cristian Riella, Jose M. Magraner, Seth L. Alper, David J. Friedman, and Martin R. Pollak. "Recruitment of APOL1 kidney disease risk variants to lipid droplets attenuates cell toxicity." Proceedings of the National Academy of Sciences 116, no. 9 (February 7, 2019): 3712–21. http://dx.doi.org/10.1073/pnas.1820414116.
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Two coding variants in the apolipoprotein L1 (APOL1) gene (termed G1 and G2) are strongly associated with increased risk of nondiabetic kidney disease in people of recent African ancestry. The mechanisms by which the risk variants cause kidney damage, although not well-understood, are believed to involve injury to glomerular podocytes. The intracellular localization and function of APOL1 in podocytes remain unclear, with recent studies suggesting possible roles in the endoplasmic reticulum (ER), mitochondria, endosomes, lysosomes, and autophagosomes. Here, we demonstrate that APOL1 also localizes to intracellular lipid droplets (LDs). While a large fraction of risk variant APOL1 (G1 and G2) localizes to the ER, a significant proportion of wild-type APOL1 (G0) localizes to LDs. APOL1 transiently interacts with numerous organelles, including the ER, mitochondria, and endosomes. Treatment of cells that promote LD formation with oleic acid shifted the localization of G1 and G2 from the ER to LDs, with accompanying reduction of autophagic flux and cytotoxicity. Coexpression of G0 APOL1 with risk variant APOL1 enabled recruitment of G1 and G2 from the ER to LDs, accompanied by reduced cell death. The ability of G0 APOL1 to recruit risk variant APOL1 to LDs may help explain the recessive pattern of kidney disease inheritance. These studies establish APOL1 as a bona fide LD-associated protein, and reveal that recruitment of risk variant APOL1 to LDs reduces cell toxicity, autophagic flux, and cell death. Thus, interventions that divert APOL1 risk variants to LDs may serve as a novel therapeutic strategy to alleviate their cytotoxic effects.
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Cornelissen, Anne, Daniela T. Fuller, Raquel Fernandez, Xiaoqing Zhao, Robert Kutys, Elizabeth Binns-Roemer, Marco Delsante, et al. "APOL1 Genetic Variants Are Associated With Increased Risk of Coronary Atherosclerotic Plaque Rupture in the Black Population." Arteriosclerosis, Thrombosis, and Vascular Biology 41, no. 7 (July 2021): 2201–14. http://dx.doi.org/10.1161/atvbaha.120.315788.
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Objective: Reported associations between kidney risk variants (G1 and G2) in APOL1 (apolipoprotein L1), encoding APOL1, and cardiovascular disease have been conflicting. We sought to explore associations of APOL1 risk variants with cause of sudden death using the CVPath Sudden Death Autopsy Registry. Approach and Results: APOL1 haplotypes and causes of sudden death, as determined through autopsy and histopathology, were obtained for 764 Black subjects. Genotyping revealed APOL1 risk alleles in 452 of 764 (59%) subjects with 347 (77%) subjects carrying one risk allele and 105 (23%) subjects harboring 2 risk alleles. APOL1 risk allele carrier status was associated with a significantly increased risk of coronary thrombosis due to plaque rupture, versus noncarriers (odds ratio for rupture, 1.655 [95% CI, 1.079–2.539]; P =0.021). Histological examinations showed coronary plaques in carriers of 2 APOL1 risk alleles had larger necrotic cores compared with noncarriers (necrotic core area/total plaque area: 46.79%±6.47% versus 20.57%±5.11%; P =0.0343 in ruptured plaques, and 41.48%±7.49% versus 18.93%±3.97%; P =0.0342 in nonruptured plaques), and immunohistochemical and immunofluorescent staining revealed APOL1-positive areas localized primarily to the necrotic core. Conclusions: APOL1 risk alleles were independently associated with an increased risk of thrombotic coronary death due to plaque rupture. Our results suggest that carriers of both 1 and 2 APOL1 risk alleles have greater accumulation of APOL1 protein within culprit plaques and greater necrotic core sizes than noncarriers. These findings suggest that APOL1 plays a role in determining plaque stability.
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Olabisi, Opeyemi A., Jia-Yue Zhang, Lynn VerPlank, Nathan Zahler, Salvatore DiBartolo, John F. Heneghan, Johannes S. Schlöndorff, et al. "APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases." Proceedings of the National Academy of Sciences 113, no. 4 (December 23, 2015): 830–37. http://dx.doi.org/10.1073/pnas.1522913113.
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Two specific genetic variants of the apolipoprotein L1 (APOL1) gene are responsible for the high rate of kidney disease in people of recent African ancestry. Expression in cultured cells of these APOL1 risk variants, commonly referred to as G1 and G2, results in significant cytotoxicity. The underlying mechanism of this cytotoxicity is poorly understood. We hypothesized that this cytotoxicity is mediated by APOL1 risk variant-induced dysregulation of intracellular signaling relevant for cell survival. To test this hypothesis, we conditionally expressed WT human APOL1 (G0), the APOL1 G1 variant, or the APOL1 G2 variant in human embryonic kidney cells (T-REx-293) using a tetracycline-mediated (Tet-On) system. We found that expression of either G1 or G2 APOL1 variants increased apparent cell swelling and cell death compared with G0-expressing cells. These manifestations of cytotoxicity were preceded by G1 or G2 APOL1-induced net efflux of intracellular potassium as measured by X-ray fluorescence, resulting in the activation of stress-activated protein kinases (SAPKs), p38 MAPK, and JNK. Prevention of net K+ efflux inhibited activation of these SAPKs by APOL1 G1 or G2. Furthermore, inhibition of SAPK signaling and inhibition of net K+ efflux abrogated cytotoxicity associated with expression of APOL1 risk variants. These findings in cell culture raise the possibility that nephrotoxicity of APOL1 risk variants may be mediated by APOL1 risk variant-induced net loss of intracellular K+ and subsequent induction of stress-activated protein kinase pathways.
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Kumar, Vinod, and Pravin C. Singhal. "APOL1 and kidney cell function." American Journal of Physiology-Renal Physiology 317, no. 2 (August 1, 2019): F463—F477. http://dx.doi.org/10.1152/ajprenal.00233.2019.
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The apolipoprotein L1 (APOL1) gene is unique to humans and gorillas and appeared ~33 million years ago. Since the majority of the mammals do not carry APOL1, it seems to be dispensable for kidney function. APOL1 renal risk variants (RRVs; G1 and G2) are associated with the development as well as progression of chronic kidney diseases (CKDs) at higher rates in populations with African ancestry. Cellular expression of two APOL1 RRVs has been demonstrated to induce cytotoxicity, including necrosis, apoptosis, and pyroptosis, in several cell types including podocytes; mechanistically, these toxicities were attributed to lysosomal swelling, K+depletion, mitochondrial dysfunction, autophagy blockade, protein kinase receptor activation, ubiquitin D degradation, and endoplasmic reticulum stress; notably, these effects were found to be dose dependent and occurred only in overtly APOL1 RRV-expressing cells. However, cellular protein expressions as well as circulating blood levels of APOL1 RRVs were not elevated in patients suffering from APOL1 RRV-associated CKDs. Therefore, the question arises as to whether it is gain or loss of function on the part of APOL1 RRVs contributing to kidney cell injury. The question seems to be more pertinent after the recognition of the role of APOL1 nonrisk (G0) in the transition of parietal epithelial cells and preservation of the podocyte molecular phenotype through modulation of the APOL1-miR-193a axis. With this background, the present review analyzed the available literature in terms of the known function of APOL1 nonrisk and how the loss of these functions could have contributed to two APOL1 RRV-associated CKDs.
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Ekulu, Pepe M., Oyindamola C. Adebayo, Jean-Paul Decuypere, Linda Bellucci, Mohamed A. Elmonem, Agathe B. Nkoy, Djalila Mekahli, et al. "Novel Human Podocyte Cell Model Carrying G2/G2 APOL1 High-Risk Genotype." Cells 10, no. 8 (July 28, 2021): 1914. http://dx.doi.org/10.3390/cells10081914.
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Apolipoprotein L1 (APOL1) high-risk genotypes (HRG), G1 and G2, increase the risk of various non-diabetic kidney diseases in the African population. To date, the precise mechanisms by which APOL1 risk variants induce injury on podocytes and other kidney cells remain unclear. Trying to unravel these mechanisms, most studies have used animal or cell models created by gene editing. We developed and characterised conditionally immortalised human podocyte cell lines derived from urine of a donor carrying APOL1 HRG G2/G2. Following induction of APOL1 expression by polyinosinic-polycytidylic acid (poly(I:C)), we assessed functional features of APOL1-induced podocyte dysfunction. As control, APOL1 wild type (G0/G0) podocyte cell line previously generated from a Caucasian donor was used. Upon exposure to poly(I:C), G2/G2 and G0/G0 podocytes upregulated APOL1 expression resulting in podocytes detachment, decreased cells viability and increased apoptosis rate in a genotype-independent manner. Nevertheless, G2/G2 podocyte cell lines exhibited altered features, including upregulation of CD2AP, alteration of cytoskeleton, reduction of autophagic flux and increased permeability in an in vitro model under continuous perfusion. The human APOL1 G2/G2 podocyte cell model is a useful tool for unravelling the mechanisms of APOL1-induced podocyte injury and the cellular functions of APOL1.
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Zhang, Jia-Yue, Minxian Wang, Lei Tian, Giulio Genovese, Paul Yan, James G. Wilson, Ravi Thadhani, et al. "UBD modifies APOL1-induced kidney disease risk." Proceedings of the National Academy of Sciences 115, no. 13 (March 12, 2018): 3446–51. http://dx.doi.org/10.1073/pnas.1716113115.
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People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1. We performed an admixture mapping study to identify genetic modifiers of APOL1-associated kidney disease. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype.
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Palusińska-Szysz, Marta, Agnieszka Zdybicka-Barabas, Rafał Luchowski, Emilia Reszczyńska, Justyna Śmiałek, Paweł Mak, Wiesław I. Gruszecki, and Małgorzata Cytryńska. "Choline Supplementation Sensitizes Legionella dumoffii to Galleria mellonella Apolipophorin III." International Journal of Molecular Sciences 21, no. 16 (August 13, 2020): 5818. http://dx.doi.org/10.3390/ijms21165818.
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The growth of Legionella dumoffii can be inhibited by Galleria mellonella apolipophorin III (apoLp-III) which is an insect homologue of human apolipoprotein E., and choline-cultured L. dumoffii cells are considerably more susceptible to apoLp-III than bacteria grown without choline supplementation. In the present study, the interactions of apoLp-III with intact L. dumoffii cells cultured without and with exogenous choline were analyzed to explain the basis of this difference. Fluorescently labeled apoLp-III (FITC-apoLp-III) bound more efficiently to choline-grown L. dumoffii, as revealed by laser scanning confocal microscopy. The cell envelope of these bacteria was penetrated more deeply by FITC-apoLp-III, as demonstrated by fluorescence lifetime imaging microscopy analyses. The increased susceptibility of the choline-cultured L. dumoffii to apoLp-III was also accompanied by alterations in the cell surface topography and nanomechanical properties. A detailed analysis of the interaction of apoLp-III with components of the L. dumoffii cells was carried out using both purified lipopolysaccharide (LPS) and liposomes composed of L. dumoffii phospholipids and LPS. A single micelle of L. dumoffii LPS was formed from 12 to 29 monomeric LPS molecules and one L. dumoffii LPS micelle bound two molecules of apoLp-III. ApoLp-III exhibited the strongest interactions with liposomes with incorporated LPS formed of phospholipids isolated from bacteria cultured on exogenous choline. These results indicated that the differences in the phospholipid content in the cell membrane, especially PC, and LPS affected the interactions of apoLp-III with bacterial cells and suggested that these differences contributed to the increased susceptibility of the choline-cultured L. dumoffii to G. mellonella apoLp-III.
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McIntosh, Tristan, Sumit Mohan, Deirdre Sawinski, Ana Iltis, and James M. DuBois. "Variation of ApoL1 Testing Practices for Living Kidney Donors." Progress in Transplantation 30, no. 1 (December 16, 2019): 22–28. http://dx.doi.org/10.1177/1526924819892917.
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Introduction: Tests exist for ApoL1 genetic variants to determine whether a potential donor’s kidneys are at increased risk of kidney failure. Variants of the ApoL1 gene associated with increased risk are primarily found in people with West African ancestry. Given uncertainty about clinical implications of ApoL1 test results for living kidney donors and recipients and the lack of uniform guidelines for ApoL1 testing, transplant centers across the United States vary in ApoL1 testing practices. Research Questions: (1) What approach do transplant centers take to determine whether prospective donors are of West African ancestry? (2)How do transplant centers engage potential donors during the ApoL1 testing process? (3) What do transplant centers identify as concerns and barriers to ApoL1 testing? and (4) What actions do transplant centers take when a potential donor has 2 ApoL1 risk variants? Design: We explored the current practices of transplant centers by surveying nephrologists and transplant surgeons at transplant centers evaluating the majority of black living donors in the United States. Results: About half of these transplant centers offered ApoL1 testing. Of those who offered ApoL1 testing, only half involved the donor in decision-making about donation when the donor has 2 risk variants. Discussion: Unaddressed differences in the priorities of transplant centers and black living donors may stigmatize black donors and undermine trust in the health-care and organ donation systems. Variation in transplant center testing practices points to the critical need for further research and community engagement to inform the development of guidelines for ApoL1 testing.
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Khatua, Atanu K., Amber M. Cheatham, Etty D. Kruzel, Pravin C. Singhal, Karl Skorecki, and Waldemar Popik. "Exon 4-encoded sequence is a major determinant of cytotoxicity of apolipoprotein L1." American Journal of Physiology-Cell Physiology 309, no. 1 (July 1, 2015): C22—C37. http://dx.doi.org/10.1152/ajpcell.00384.2014.
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The apolipoprotein L1 (APOL1) gene ( APOL1) product is toxic to kidney cells, and its G1 and G2 alleles are strongly associated with increased risk for kidney disease progression in African Americans. Variable penetrance of the G1 and G2 risk alleles highlights the significance of additional factors that trigger or modify the progression of disease. In this regard, the effect of alternative splicing in the absence or presence of G1 or G2 alleles is unknown. In this study we investigated whether alternative splicing of non-G1, non-G2 APOL1 ( APOL1 G0) affects its biological activity. Among seven APOL1 exons, exons 2 and 4 are differentially expressed in major transcripts. We found that, in contrast to APOL1 splice variants B3 or C, variants A and B1 demonstrate strong toxicity in human embryonic kidney (HEK293T) cells. Subsequently, we established that exon 4 is a major determinant of toxicity of variants A and B1 and that extracellular release of these variants is dispensable for their cytotoxicity. Although only variants A and B1 induced nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, exon 4-positive and -negative APOL1 variants stimulated perinuclear accumulation of unprocessed autophagosomes. Knockdown of endogenous TFEB did not attenuate APOL1 cytotoxicity, indicating that nuclear translocation of TFEB is dispensable for APOL1 toxicity. Our findings that a human podocyte cell line expresses exon 4-positive and -negative APOL1 transcripts suggest that these variants may play a differential role in podocyte pathology. In summary, we have identified exon 4 as a major determinant of APOL1 G0 cytotoxicity.
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Young, Bessie A., Erika Blacksher, Kerri L. Cavanaugh, Barry I. Freedman, Stephanie M. Fullerton, Jeffrey B. Kopp, Ebele M. Umeukeje, Kathleen M. West, James G. Wilson, and Wylie Burke. "Apolipoprotein L1 Testing in African Americans: Involving the Community in Policy Discussions." American Journal of Nephrology 50, no. 4 (2019): 303–11. http://dx.doi.org/10.1159/000502675.
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Background: Apolipoprotein A1 (APOL1) gene variants occurring in people of West African descent contribute to the greater burden of kidney disease among African Americans. These variants are associated with increased risk of nondiabetic nephropathy, more rapid progression of chronic kidney disease, and shorter survival of donor kidneys after transplantation. However, only a minority of people with APOL1-associated risk develops kidney disease and specific clinical measures to address APOL1-associated risk are lacking. Given these uncertainties, we sought to engage members of the African American public in discussions with other stakeholders about the appropriate use of APOL1 testing. Methods: Formative interviews with community members, researchers, and clinicians in Seattle WA, Nashville TN, and Jackson MS, provided baseline information about views toward APOL1 testing and informed the design of 3 community-based deliberations among African Americans. A national meeting held in March 2018 included 13 community members, 7 scientific advisors and 26 additional researchers, clinicians, bioethicists, patient advocates, and representatives from professional organizations and federal funding agencies. Using small break-out and plenary discussion, the group agreed on recommendations based on current knowledge about APOL1-associated risk. Results: Meeting outcomes included recommendations to develop educational materials about APOL1 for community members and clinicians; to offer APOL1 research results to participants; and on the use of APOL1testing in kidney transplant programs. The group recommended against the routine offer of APOL1 testing in clinical care. Areas of disagreement included whether kidney transplant programs should require APOL1 testing of prospective living donors or bar individuals with APOL1 risk from donating kidneys and whether testing should be available on request in routine clinical care. Conclusion: We recommend continued discussion among stakeholders and concerted efforts to ensure active and informed participation of members of the affected community to guide research on APOL1 and kidney disease.
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Anderson, Blair R., Erica E. Davis, Marilyn J. Telen, and Allison E. Ashley-Koch. "Evidence for a Dominant Negative Effect Conferred By the APOL1 G2 Sickle Cell Nephropathy Risk Allele in an in Vivo Model." Blood 124, no. 21 (December 6, 2014): 1374. http://dx.doi.org/10.1182/blood.v124.21.1374.1374.
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Abstract BACKGROUND: Sickle cell disease (SCD) patients have a heterogeneous clinical course, and as patient survival has improved, end-organ damage has become an emergent clinical priority. End stage renal disease (ESRD), occurring in 5-18% of SCD patients, is a particular concern, because it is a major risk factor for early mortality (Platt et al. 1994). Detection of SCD nephropathy (SCDN) relies on relatively late-stage markers, namely proteinuria and reduced glomerular filtration rate (GFR). Consequently, at-risk SCD patients are not identified prior to end-organ damage. In non-SCD nephropathy, ESRD risk among African American individuals has been attributed to coding variants (termed G1 and G2) in apolipoprotein L1 (APOL1). The G1 allele consists of two nonsynonymous variants in perfect LD, rs73885319 and rs60910145 (encoding S384G and I384M), while the G2 variant consists of a six base pair deletion removing amino acids N388 and Y389 (~21% and ~13% allelic frequency in African Americans for G1 and G2, respectively). We demonstrated that these variants in APOL1 are strong predictors of risk for proteinuria in SCD (Ashley-Koch et al. 2011). Here, we use zebrafish as an in vivo model to both examine the role of apol1 in glomerular development and pronephric filtration and also to test the effects of APOL1 G1 and G2 expression in the developing kidney. METHODS: A morpholino (MO) was designed by Gene Tools, LLC (Philomath, OR) to target the translation initiation site of zebrafish apol1. APOL1 G1 and G2 allelic constructs were synthesized from a wild-type (WT) APOL1 human open reading frame clone (GenBank: BC112943) using site-directed mutagenesis (Stratagene, QuikChange II), subsequently transcribed (mMESSAGE mMACHINE®, Life Technologies) into capped mRNA and co-injected with apol1-MO into zebrafish embryos. To assay glomerular filtration, 70 kDa FITC-conjugated dextran was injected into the cardiac venous sinus of 48 hour post-fertilization embryos. The eye vasculature of individual fish was imaged at two, 12, and 36 hours after dextran injection. The average fluorescence intensity was measured across the eye, and changes in intensity relative to the 2-hour post-injection measurements were calculated for comparison. Electron microscopy sections of five days post-fertilization embryos were cut on a Leica-Reichert Ultracut E ultramicrotome, and semi-thin sections (1.0μm) were stained and examined on a Phillips CM12 electron microscope. RESULTS: As we showed previously (Anderson et al., ASH 2013), MO-induced suppression of apol1 in zebrafish embryos results in pericardial edema, glomerular filtration defects, and extensive podocyte loss. Importantly, complementation of apol1 morphants with WT human APOL1 mRNA rescues the observed kidney defects. However, we now show that neither APOL1 G1 nor G2 risk alleles ameliorate defects caused by apol1 suppression. Notably, injection of APOL1 G2 alone results in renal defects, as indicated by increased dextran clearance and the presence of microvillus protrusions in the urinary space. Injection of APOL1 G1 alone, however, does not induce noticeable kidney dysfunction. Furthermore, when APOL1 G2 injected embryos were titrated with increasing concentrations of human APOL1 WT mRNA, we observed a significant reduction of edema formation in developing embryos, suggesting a possible dominant-negative effect of the altered protein. CONCLUSIONS: Unlike the WT APOL1 mRNA, neither the APOL1 G1 or G2 risk alleles could rescue kidney dysfunction due to knockdown of apol1 in zebrafish embryos, suggesting that these SCDN risk alleles impact the normal function of APOL1 in the kidney. Furthermore, development of edema with concomitant defects in glomerular ultrastructure in zebrafish embryos injected with APOL1 G2 mRNA alone suggest that this allele may act in a dominant-negative manner to induce kidney defects. Interestingly, it has been shown that APOL1 may cause toxic renal effects through programmed cell death pathways leading to glomerulosclerosis (Wan et al. 2008). Thus, apol1 suppression could result in the dysregulation of autophagic pathways, causing podocyte malformation and thereby affecting the susceptibility of the pronephros to glomerular injury. In summary, these data provide essential insight into the biological mechanisms by which APOL1 variants confer disease risk in human SCDN and other nondiabetic nephropathies. Disclosures No relevant conflicts of interest to declare.
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Zhu, Hua, Xinyao Hu, Shi Feng, Yuntao Li, Yonggang Zhang, Sheng Qiu, Ran Chen, et al. "APOL4, a Novel Immune-Related Prognostic Biomarker for Glioma." Journal of Clinical Medicine 11, no. 19 (September 29, 2022): 5765. http://dx.doi.org/10.3390/jcm11195765.
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Glioma is the common, most aggressive and poorest prognostic tumor type in the brain. More and more biomarkers associated with glioma treatment, prognosis, and immunity are being discovered. Here, we aimed to explore the underlying biological functions and prognostic predictive value of Apolipoprotein L4 (APOL4) in glioma. We downloaded the expression data of APOL4 and clinical information from several databases and used R software for preprocessing. The clinical significance of APOL4 in a glioma outcome was explored by the Cox regression analysis and Kaplan–Meier survival analysis. In addition, immune infiltrates and microenvironmental indicators were assessed by CIBERSORT and TIMER. GO and KEGG analyses were used to analyze the potential functions of APOL4 in gliomas. APOL4 expression was increased in glioma specimens compared to normal tissues and correlated dramatically with the WHO grade. A survival analysis showed a shorter overall survival (OS) in glioma patients with APOL4 overexpression, and a Cox regression analysis showed that APOL4 was an independent prognostic factor for the OS of glioma patients. GSEA, GO, and KEGG enrichment analyses showed remarkable enrichment in immune-related pathways. APOL4 expression was positively correlated with immune infiltration (including DC cells, neutrophils, CD8+ T cells, B cells, macrophages, CD4+ T cells, etc.) and microenvironmental parameters (including immune, stromal, and ESTIMATE scores) in gliomas. Glioma patients with a higher expression of APOL4 may be more sensitive to immune checkpoint inhibitors (ICI). In conclusion, these findings suggest that APOL4 is associated with the tumor grade and immune infiltrates; APOL4 may be a new and potential biomarker for therapeutic and prognostic evaluations that may further suggest the therapeutic efficacy of immunotherapy.
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Raghubeer, Shanel, Tahir S. Pillay, and Tandi Edith Matsha. "Gene of the month: APOL1." Journal of Clinical Pathology 73, no. 8 (May 13, 2020): 441–43. http://dx.doi.org/10.1136/jclinpath-2020-206517.
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Apolipoprotein L1 (APOL1) is a protein encoded by the APOL1 gene, found only in humans and several primates. Two variants encoding two different isoforms exist for APOL1, namely G1 and G2. These variants confer increased protection against trypanosome infection, and subsequent African sleeping sickness, and also increase the likelihood of renal disease in individuals of African ancestry. APOL1 mutations are associated with increased risk of chronic kidney disease, inflammation, and exacerbation of systemic lupus erythematosus-associated renal dysfunction. This review serves to outline the structure and function of APOL1, as well as its role in several disease outcomes.
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Palusińska-Szysz, Marta, Agnieszka Zdybicka-Barabas, Magdalena Frąc, Wiesław I. Gruszecki, Sylwia Wdowiak-Wróbel, Emilia Reszczyńska, Dorota Skorupska, Paweł Mak, and Małgorzata Cytryńska. "Identification and characterization of Staphylococcus spp. and their susceptibility to insect apolipophorin III." Future Microbiology 15, no. 11 (July 2020): 1015–32. http://dx.doi.org/10.2217/fmb-2019-0328.
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Aim: This study investigated the effect of an insect antimicrobial protein, apolipophorin III (apoLp-III), against two newly isolated, identified and characterized clinical strains of Staphylococcus spp. Materials & methods: Both strains were identified by 16S rRNA sequencing and metabolic and phenotypic profiling. The antibacterial activity of apoLp-III was tested using a colony counting assay. ApoLp-III interaction with bacterial cell surface was analyzed by Fourier transform IR spectroscopy. Results: Staphylococcus epidermidis and Staphylococcus capitis were identified. ApoLp-III exerted a dose-dependent bactericidal effect on the tested strains. The differences in the Staphylococcus spp. surface components may contribute to the various sensitivities of these strains to apoLp-III. Conclusion: ApoLp-III may provide a baseline for development of antibacterial preparations against Staphylococcus spp. involved in dermatological problems.
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Shah, Shrijal S., Herbert Lannon, Leny Dias, Jia-Yue Zhang, Seth L. Alper, Martin R. Pollak, and David J. Friedman. "APOL1 Kidney Risk Variants Induce Cell Death via Mitochondrial Translocation and Opening of the Mitochondrial Permeability Transition Pore." Journal of the American Society of Nephrology 30, no. 12 (September 26, 2019): 2355–68. http://dx.doi.org/10.1681/asn.2019020114.
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BackgroundGenetic Variants in Apolipoprotein L1 (APOL1) are associated with large increases in CKD rates among African Americans. Experiments in cell and mouse models suggest that these risk-related polymorphisms are toxic gain-of-function variants that cause kidney dysfunction, following a recessive mode of inheritance. Recent data in trypanosomes and in human cells indicate that such variants may cause toxicity through their effects on mitochondria.MethodsTo examine the molecular mechanisms underlying APOL1 risk variant–induced mitochondrial dysfunction, we generated tetracycline-inducible HEK293 T-REx cells stably expressing the APOL1 nonrisk G0 variant or APOL1 risk variants. Using these cells, we mapped the molecular pathway from mitochondrial import of APOL1 protein to APOL1-induced cell death with small interfering RNA knockdowns, pharmacologic inhibitors, blue native PAGE, mass spectrometry, and assessment of mitochondrial permeability transition pore function.ResultsWe found that the APOL1 G0 and risk variant proteins shared the same import pathway into the mitochondrial matrix. Once inside, G0 remained monomeric, whereas risk variant proteins were prone to forming higher-order oligomers. Both nonrisk G0 and risk variant proteins bound components of the mitochondrial permeability transition pore, but only risk variant proteins activated pore opening. Blocking mitochondrial import of APOL1 risk variants largely eliminated oligomer formation and also rescued toxicity.ConclusionsOur study illuminates important differences in the molecular behavior of APOL1 nonrisk and risk variants, and our observations suggest a mechanism that may explain the very different functional effects of these variants, despite the lack of consistently observed differences in trafficking patterns, intracellular localization, or binding partners. Variant-dependent differences in oligomerization pattern may underlie APOL1’s recessive, gain-of-function biology.
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Ge, Mengyuan, Judith Molina, G. Michelle Ducasa, Shamroop K. Mallela, Javier Varona Santos, Alla Mitrofanova, Jin-Ju Kim, et al. "APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis." Human Molecular Genetics 30, no. 3-4 (January 30, 2021): 182–97. http://dx.doi.org/10.1093/hmg/ddab022.
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Abstract Lipotoxicity was recently reported in several forms of kidney disease, including focal segmental glomerulosclerosis (FSGS). Susceptibility to FSGS in African Americans is associated with the presence of genetic variants of the Apolipoprotein L1 gene (APOL1) named G1 and G2. If and how endogenous APOL1 may alter mitochondrial function by the modifying cellular lipid metabolism is unknown. Using transgenic mice expressing the APOL1 variants (G0, G1 or G2) under endogenous promoter, we show that APOL1 risk variant expression in transgenic mice does not impair kidney function at baseline. However, APOL1 G1 expression worsens proteinuria and kidney function in mice characterized by the podocyte inducible expression of nuclear factor of activated T-cells (NFAT), which we have found to cause FSGS. APOL1 G1 expression in this FSGS-model also results in increased triglyceride and cholesterol ester contents in kidney cortices, where lipid accumulation correlated with loss of renal function. In vitro, we show that the expression of endogenous APOL1 G1/G2 in human urinary podocytes is associated with increased cellular triglyceride content and is accompanied by mitochondrial dysfunction in the presence of compensatory oxidative phosphorylation (OXPHOS) complexes elevation. Our findings indicate that APOL1 risk variant expression increases the susceptibility to lipid-dependent podocyte injury, ultimately leading to mitochondrial dysfunction.
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Liu, Esther, Behram Radmanesh, Byungha H. Chung, Michael D. Donnan, Dan Yi, Amal Dadi, Kelly D. Smith, et al. "Profiling APOL1 Nephropathy Risk Variants in Genome-Edited Kidney Organoids with Single-Cell Transcriptomics." Kidney360 1, no. 3 (February 18, 2020): 203–15. http://dx.doi.org/10.34067/kid.0000422019.
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BackgroundDNA variants in APOL1 associate with kidney disease, but the pathophysiologic mechanisms remain incompletely understood. Model organisms lack the APOL1 gene, limiting the degree to which disease states can be recapitulated. Here we present single-cell RNA sequencing (scRNA-seq) of genome-edited human kidney organoids as a platform for profiling effects of APOL1 risk variants in diverse nephron cell types.MethodsWe performed footprint-free CRISPR-Cas9 genome editing of human induced pluripotent stem cells (iPSCs) to knock in APOL1 high-risk G1 variants at the native genomic locus. iPSCs were differentiated into kidney organoids, treated with vehicle, IFN-γ, or the combination of IFN-γ and tunicamycin, and analyzed with scRNA-seq to profile cell-specific changes in differential gene expression patterns, compared with isogenic G0 controls.ResultsBoth G0 and G1 iPSCs differentiated into kidney organoids containing nephron-like structures with glomerular epithelial cells, proximal tubules, distal tubules, and endothelial cells. Organoids expressed detectable APOL1 only after exposure to IFN-γ. scRNA-seq revealed cell type–specific differences in G1 organoid response to APOL1 induction. Additional stress of tunicamycin exposure led to increased glomerular epithelial cell dedifferentiation in G1 organoids.ConclusionsSingle-cell transcriptomic profiling of human genome-edited kidney organoids expressing APOL1 risk variants provides a novel platform for studying the pathophysiology of APOL1-mediated kidney disease.
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Thomson, Russell, and Alan Finkelstein. "Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: Relevance to trypanosome lysis." Proceedings of the National Academy of Sciences 112, no. 9 (February 17, 2015): 2894–99. http://dx.doi.org/10.1073/pnas.1421953112.
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Apolipoprotein L-1 (APOL1), the trypanolytic factor of human serum, can lyse several African trypanosome species includingTrypanosoma brucei brucei, but not the human-infective pathogensT. brucei rhodesienseandT. brucei gambiense, which are resistant to lysis by human serum. Lysis follows the uptake of APOL1 into acidic endosomes and is apparently caused by colloid-osmotic swelling due to an increased ion permeability of the plasma membrane. Here we demonstrate that nanogram quantities of full-length recombinant APOL1 induce ideally cation-selective macroscopic conductances in planar lipid bilayers. The conductances were highly sensitive to pH: their induction required acidic pH (pH 5.3), but their magnitude could be increased 3,000-fold upon alkalinization of the milieu (pKa= 7.1). We show that this phenomenon can be attributed to the association of APOL1 with the bilayer at acidic pH, followed by the opening of APOL1-induced cation-selective channels upon pH neutralization. Furthermore, the conductance increase at neutral pH (but not membrane association at acidic pH) was prevented by the interaction of APOL1 with the serum resistance-associated protein, which is produced byT. brucei rhodesienseand prevents trypanosome lysis by APOL1. These data are consistent with a model of lysis that involves endocytic recycling of APOL1 and the formation of cation-selective channels, at neutral pH, in the parasite plasma membrane.
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Akhavan Sepahi, Mohsen, LVKS Bhaskar, Audrey Tolouian, and Ramin Tolouian. "Apolipoprotein L1 associated nephropathy; an overview." Journal of Renal Injury Prevention 8, no. 4 (November 15, 2019): 311–15. http://dx.doi.org/10.15171/jrip.2019.57.
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Genetic variants of apolipoprotein L1 (APOL1) have been recognized as a risk factor for kidney disease in people of African ancestry. APOL1 mediate renal damage in podocytes through necrosis, apoptosis and pyroptosis processes. APOL1 gene contains G1 and G2 alleles that mediate in increasing risk of renal disorders in African Americans. People who carry APOL1 risk alleles have a three to four-fold increase risk for non-diabetic renal disease (NDRD), Idiopathic focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy (HIVAN). Therefore, identifying genetic factors involved in the pathogenesis of renal disorders, including APOL1 risk variants, may help to improve our understanding of kidney problems.
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Chaudhary, Ninad S., Justin X. Moore, Neil A. Zakai, Suzanne E. Judd, Rakhi P. Naik, Sophie Limou, Mary Cushman, et al. "APOL1 Nephropathy Risk Alleles and Risk of Sepsis in Blacks." Clinical Journal of the American Society of Nephrology 14, no. 12 (November 8, 2019): 1733–40. http://dx.doi.org/10.2215/cjn.04490419.
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Background and objectivesapo L1 (APOL1) nephropathy risk alleles are associated with CKD in blacks. Although APOL1 has innate immune functions, little is known about the association of APOL1 genotypes with risk of infectious outcomes, such as sepsis. The objective of this study was to examine the associations of APOL1 nephropathy risk alleles with risk of sepsis in black adults.Design, setting, participants, & measurementsWe assessed the association of APOL1 risk alleles with incident sepsis in 10,366 black participants of the Reasons for Geographic and Racial Differences in Stroke study enrolled between 2003 and 2007 with follow-up through December 31, 2012. In Cox models adjusted for demographics, comorbid conditions, and principal components ancestry, we examined the association of APOL1 risk alleles with incident sepsis using recessive (comparing zero or one versus two risk alleles), dominant (zero versus one or two risk alleles), and additive genetic models. We also examined models stratified by diabetes and CKD status.ResultsA total of 1320 (13%) participants had two APOL1 risk alleles, 4719 (46%) had one risk allele, and 4327 (42%) participants had zero risk alleles. A total of 306 sepsis events occurred over a median 6.5 years (interquartile range, 4.5–8.1). There were no statistically significant associations of APOL1 genotype with sepsis risk under recessive genetic models. APOL1 genotypes were associated with sepsis risk under dominant (hazard ratio, 1.55; 95% confidence interval, 1.13 to 2.11) and additive (hazard ratio per variant allele copy, 1.25; 95% confidence interval, 1.02 to 1.53) genetic models adjusted for covariates and ancestry. These associations did not vary by diabetes or CKD status (Pinteraction>0.10 for both).ConclusionsIn community-dwelling black adults, carriage of APOL1 nephropathy risk alleles are common and associated with higher risk of sepsis.
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Bruggeman, Leslie A., John F. O’Toole, and John R. Sedor. "APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?" American Journal of Physiology-Renal Physiology 316, no. 1 (January 1, 2019): F1—F8. http://dx.doi.org/10.1152/ajprenal.00426.2018.
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The mechanism that explains the association of APOL1 variants with nondiabetic kidney diseases in African Americans remains unclear. Kidney disease risk is inherited as a recessive trait, and many studies investigating the intracellular function of APOL1 have indicated the APOL1 variants G1 and G2 are associated with cytotoxicity. Whether cytotoxicity results from the absence of a protective effect conferred by the G0 allele or is induced by a deleterious effect of variant allele expression has not be conclusively established. A central issue hampering basic biology studies is the lack of model systems that authentically replicate APOL1 expression patterns. APOL1 is present in humans and a few other primates and appears to have important functions in the kidney, as the kidney is the primary target for disease associated with the genetic variance. There have been no studies to date assessing the function of untagged APOL1 protein under native expression in human or primate kidney cells, and no studies have examined the heterozygous state, a disease-free condition in humans. A second major issue is the chronic kidney disease (CKD)-associated APOL1 variants are conditional mutations, where the disease-inducing function is only evident under the appropriate environmental stimulus. In addition, it is possible there may be more than one mechanism of pathogenesis that is dependent on the nature of the stressor or other genetic variabilities. Studies addressing the function of APOL1 and how the CKD-associated APOL1 variants cause kidney disease are challenging and remain to be fully investigated under conditions that faithfully model known human genetics and physiology.
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Wang, Hanghang, Patrick H. Pun, Lydia Kwee, Damian Craig, Carol Haynes, Megan Chryst-Ladd, Laura P. Svetkey, et al. "Apolipoprotein L1 Genetic Variants Are Associated with Chronic Kidney Disease but Not with Cardiovascular Disease in a Population Referred for Cardiac Catheterization." Cardiorenal Medicine 7, no. 2 (December 29, 2016): 96–103. http://dx.doi.org/10.1159/000453458.
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Background: While the association between APOL1 genetic variants and chronic kidney disease (CKD) has been established, their association with cardiovascular disease (CVD) is unclear. This study sought to understand CKD and cardiovascular risk conferred by APOL1 variants in a secondary cardiovascular prevention population. Methods: Two risk variants in APOL1 were genotyped in African-Americans (n = 1,641) enrolled in the CATHGEN biorepository, comprised of patients referred for cardiac catheterization at Duke University Hospital, Durham, NC, USA (2001-2010). Individuals were categorized as noncarriers (n = 722), heterozygote (n = 771), or homozygote carriers (n = 231) of APOL1 risk alleles. Multivariable logistic regression and Cox proportional hazards models adjusted for CVD risk factors were used to assess the association between APOL1 risk variants and prevalent and incident CKD, prevalent coronary artery disease (CAD), incident CVD events, and mortality. Results: The previously identified association between APOL1 variants and prevalent CKD was confirmed (OR: 1.85, 95% CI: 1.33-2.57, p = 0.0002). No statistically significant associations were detected between APOL1 variants and incident CKD or prevalent CAD, incident CVD events or mortality. Age, type 2 diabetes, and ejection fraction at baseline were significant clinical factors that predicted the risk of incident CKD in a subgroup analysis of APOL1 homozygous individuals. Conclusion:APOL1 genetic variants are not associated with CAD or incident CVD events in a cohort of individuals with a high burden of cardiometabolic risk factors. In individuals with homozygous APOL1 status, factors that predicted subsequent CKD included age, presence of type 2 diabetes, and ejection fraction at baseline.
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Davis, Shamara E., Atanu Khatua, and Waldemar Popik. "Nucleosomal double-stranded DNA triggers APOL1 expression through the STINGTBK1-IRF3 pathway." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 63.2. http://dx.doi.org/10.4049/jimmunol.202.supp.63.2.
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Abstract African Americans are four times more likely to develop kidney disease. Racial disparities in the frequency of nondiabetic kidney disease has led to the discovery of the apolipoprotein L1 (APOL1) gene variants, G1 and G2, which exist exclusively in individuals of recent African ancestry. The presence of these kidney risk alleles strongly correlates with several forms of nondiabetic kidney disease including lupus nephritis (LN). However, the mechanism by which APOL1 variants lead to a faster progression to LN in systemic lupus erythematosus (SLE) patients carrying APOL1 risk alleles is unclear. Increased levels of type I interferons (IFNs) and nucleosomal dsDNA fragments (nsDNA) in the blood is the hallmark of lupus erythematosus. We hypothesize that accumulation of dsDNA in the cytosol of podocytes that play a key role in maintenance of the filtration barrier in the kidney activates the DNA sensing pathways leading to expression of type I IFNs and proinflammatory cytokines damaging podocytes. Although type I IFNs stimulate APOL1 expression, it is unknown whether dsDNA induces APOL1 accumulation independently of IFN. Here we show that nsDNA triggers the expression of APOL1 through the activation of the cGAS/IFI16-STING-TBK1-IRF3 pathway. We have also shown that inhibition of type I IFN only partly inhibited APOL1 accumulation in podocytes, demonstrating that nsDNA directly activates expression of the APOL1 gene. We conclude that blocking type I IFN signaling and targeting elements of the nsDNA-induced pathway may represent a novel therapeutic approach to inhibit LN progression in African Americans SLE patients carrying APOL1 kidney risk alleles.
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O'Toole, John F., William Schilling, Diana Kunze, Sethu M. Madhavan, Martha Konieczkowski, Yaping Gu, Liping Luo, Zhenzhen Wu, Leslie A. Bruggeman, and John R. Sedor. "ApoL1 Overexpression Drives Variant-Independent Cytotoxicity." Journal of the American Society of Nephrology 29, no. 3 (November 27, 2017): 869–79. http://dx.doi.org/10.1681/asn.2016121322.
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Coding variants in the APOL1 gene are associated with kidney diseases in African ancestral populations; yet, the underlying biologic mechanisms remain uncertain. Variant-dependent autophagic and cytotoxic cell death have been proposed as pathogenic pathways mediating kidney injury. To examine this possibility, we conditionally expressed APOL1-G0 (reference), -G1, and -G2 (variants) using a tetracycline-regulated system in HEK293 cells. Autophagy was monitored biochemically and cell death was measured using multiple assays. We measured intracellular Na+ and K+ content with atomic absorption spectroscopy and APOL1-dependent currents with whole-cell patch clamping. Neither reference nor variant APOL1s induced autophagy. At high expression levels, APOL1-G0, -G1, and -G2 inserted into the plasma membrane and formed pH-sensitive cation channels, causing collapse of cellular Na+ and K+ gradients, phosphorylation of p38 mitogen-activated protein kinase, and cell death, without variant-dependent differences. APOL1-G0 and -G2 exhibited similar channel properties in whole-cell patch clamp experiments. At low expression levels, neither reference nor variant APOL1s localized on the plasma membrane, Na+ and K+ gradients were maintained, and cells remained viable. Our results indicate that APOL1-mediated pore formation is critical for the trypanolytic activity of APOL1 and drives APOL1-mediated cytotoxicity in overexpression systems. The absence of cytotoxicity at physiologic expression levels suggests variant-dependent intracellular K+ loss and cytotoxicity does not drive kidney disease progression.
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Zahr, Rima, Jeffrey Lebensburger, Evadnie Rampersaud, Jane S. Hankins, and Jeremie H. Estepp. "Children with Sickle Cell Anemia and APOL1 Gene Variants Develop Albuminuria Early in Life." Blood 132, Supplement 1 (November 29, 2018): 2377. http://dx.doi.org/10.1182/blood-2018-99-118912.
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Abstract Introduction: Gene variants in the apolipoprotein L-1 (APOL1) gene are strong modifiers for the development of chronic kidney disease in individuals of African descent and are associated with progression of renal disease and albuminuria in cross-sectional studies of individuals with sickle cell anemia (SCA). While the association of APOL1 with albuminuria in older SCA patients is established, it is unclear whether participants with APOL1 G1 (rs73885319/ rs6090145) and G2 (rs71785313) variants (Ashley-Koch Br J Hematol 2011; Kormann Br J Haematol 2017) are more likely to develop albuminuria early in life. We hypothesized that individuals with SCA with the APOL1 G1 and G2 variants experience albuminuria at a higher rate and at a younger age than individuals without these APOL1 mutations. Methods: APOL1 G1 (rs73885319/ rs6090145) and G2 (rs71785313) variants were identified from whole genome sequence (WGS) data for individuals with SCA (HbSS or HbSβ0 thalassemia) enrolled in the longitudinal Sickle Cell Clinical Research and Intervention Program (SCCRIP; NCT02098863) (Hankins et al, Pediatr Blood Cancer 2018). WGS data were generated by aligning paired-end 150 bp reads to the GRCh38 human reference using the Burrows-Wheeler Aligner (BWA-ALN v0.7.12) and the GATK best-practices workflow implemented in GATK v3.4.0. We modeled the time to first albuminuria diagnosis defined by abnormal urine albumin:creatinine ratio (>30mg/g). Covariates included age, sex, and hydroxyurea therapy. We considered two risk models. Model 1 defined high risk APOL1 mutation as either APOL1 G1 homozygotes or G2 homozygotes or G1/G2 double heterozygotes. Model 2 was defined additively wherein G1 or G2 homozygotes were assumed to confer more risk compared to G1/G2 double heterozygotes. Results: In 285 individuals with SCA, 93% (n=266) with HbSS and 7% (n=19) with HbSβ0 thalassemia, 14% (n=41) experienced albuminuria at a mean age of 11.4 (±3.3) years. In total, 11% (n=32) of this SCA cohort had an APOL1 mutation; 6% (n=17) were G1/G2 double heterozygote, 4% (n=11) were G1 homozygotes, and 1% (n=4) were G2 homozygotes. Among the 32 participants with an APOL1 mutation, 40% (n=13) had albuminuria as compared to 11% (n=28) of the 253 participants without an APOL1 mutation (OR: 9.85, 95% CI 3.84-25.25). There was also a significant association with albuminuria based on the additive genetic model (OR: 4.38, 95% CI 2.39 -8.02) (Table). In a survival analysis, participants with an APOL1 mutation had a hazard ratio (HR) of 3.75 (95% CI: 1.93-7.29, p<0.0001) associated with time to diagnosis of albuminuria compared with individuals with other non-risk APOL1 genotypes. The mean age for individuals having albuminuria with APOL1 G1/G2 risk alleles was 9.8 (±3.2) years, roughly 2 years younger than those without the risk alleles (11.8 ±4.7 years) (Satterthwaite t value=3.10, p=0.003). APOL1 G1 alleles also contributed individual risk of albuminuria (HR=1.66, p=0.0374). Summary: Our analyses found that pediatric individuals with SCA who have APOL1 two risk alleles are at high risk of developing albuminuria which many will experience early in childhood. This important finding has significant implications for clinical care. First, using a genetic screening program for all patients with SCAC can identify individuals with APOL1 mutations. Second, individuals with SCA and an APOL1 mutation should be screened for albuminuria during childhood. Finally, early initiation of therapeutic strategies to ameliorate renal dysfunction needs to be evaluated in the presence of APOL1 mutations. Figure. Figure. Disclosures Hankins: Global Blood Therapeutics: Research Funding; Novartis: Research Funding; NCQA: Consultancy; bluebird bio: Consultancy. Estepp:ASH Scholar: Research Funding; Daiichi Sankyo: Consultancy; NHLBI: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding.
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Friedman, David J., and Martin R. Pollak. "APOL1 and Kidney Disease: From Genetics to Biology." Annual Review of Physiology 82, no. 1 (February 10, 2020): 323–42. http://dx.doi.org/10.1146/annurev-physiol-021119-034345.
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Genetic variants in the APOL1 gene, found only in individuals of recent African ancestry, greatly increase risk of multiple types of kidney disease. These APOL1 kidney risk alleles are a rare example of genetic variants that are common but also have a powerful effect on disease susceptibility. These alleles rose to high frequency in sub-Saharan Africa because they conferred protection against pathogenic trypanosomes that cause African sleeping sickness. We consider the genetic evidence supporting the association between APOL1 and kidney disease across the range of clinical phenotypes in the APOL1 nephropathy spectrum. We then explore the origins of the APOL1 risk variants and evolutionary struggle between humans and trypanosomes at both the molecular and population genetic level. Finally, we survey the rapidly growing literature investigating APOL1 biology as elucidated from experiments in cell-based systems, cell-free systems, mouse and lower organism models of disease, and through illuminating natural experiments in humans.
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Doshi, Mona D., Mariella Ortigosa-Goggins, Amit X. Garg, Lihua Li, Emilio D. Poggio, Cheryl A. Winkler, and Jeffrey B. Kopp. "APOL1 Genotype and Renal Function of Black Living Donors." Journal of the American Society of Nephrology 29, no. 4 (January 16, 2018): 1309–16. http://dx.doi.org/10.1681/asn.2017060658.
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Black living kidney donors are at higher risk of developing kidney disease than white donors. We examined the effect of the APOL1 high-risk genotype on postdonation renal function in black living kidney donors and evaluated whether this genotype alters the association between donation and donor outcome. We grouped 136 black living kidney donors as APOL1 high-risk (two risk alleles; n=19; 14%) or low-risk (one or zero risk alleles; n=117; 86%) genotype. Predonation characteristics were similar between groups, except for lower mean±SD baseline eGFR (CKD-EPI equation) in donors with the APOL1 high-risk genotype (98±17 versus 108±20 ml/min per 1.73 m2; P=0.04). At a median of 12 years after donation, donors with the APOL1 high-risk genotype had lower eGFR (57±18 versus 67±15 ml/min per 1.73 m2; P=0.02) and faster decline in eGFR after adjusting for predonation eGFR (1.19; 95% confidence interval, 0 to 2.3 versus 0.4; 95% confidence interval, 0.1 to 0.7 ml/min per 1.73 m2 per year, P=0.02). Two donors developed ESRD; both carried the APOL1 high-risk genotype. In a subgroup of 115 donors matched to 115 nondonors by APOL1 genotype, we did not find a difference between groups in the rate of eGFR decline (P=0.39) or any statistical interaction by APOL1 status (P=0.92). In conclusion, APOL1 high-risk genotype in black living kidney donors associated with greater decline in postdonation kidney function. Trajectory of renal function was similar between donors and nondonors. The association between APOL1 high-risk genotype and poor renal outcomes in kidney donors requires validation in a larger study.
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Lee, Hewang, Hila Roshanravan, Ying Wang, Koji Okamoto, Junghwa Ryu, Shashi Shrivastav, Peng Qu, and Jeffrey B. Kopp. "ApoL1 renal risk variants induce aberrant THP-1 monocyte differentiation and increase eicosanoid production via enhanced expression of cyclooxygenase-2." American Journal of Physiology-Renal Physiology 315, no. 1 (July 1, 2018): F140—F150. http://dx.doi.org/10.1152/ajprenal.00254.2017.
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Apolipoprotein L1 ( ApoL1) genetic variants are strongly associated with kidney diseases. We investigated the role of ApoL1 variants in monocyte differentiation and eicosanoid production in macrophages, as activated tissue macrophages in kidney might contribute to kidney injury. In human monocyte THP-1 cells, transient overexpression of ApoL1 (G0, G1, G2) by transfection resulted in a 5- to 11-fold increase in CD14 and CD68 gene expression, similar to that seen with phorbol-12-myristate acetate treatment. All ApoL1 variants caused monocytes to differentiate into atypical M1 macrophages with marked increase in M1 markers CD80, TNF, IL1B, and IL6 and modest increase in the M2 marker CD163 compared with control cells. ApoL1-G1 transfection induced additional CD206 and TGFB1 expression, and ApoL1-G2 transfection induced additional CD204 and TGFB1 expression. Gene expression of prostaglandin E2 (PGE2) synthase and thromboxane synthase and both gene and protein expression of cyclooxygenase-2 (COX-2) were increased by ApoL1-G1 and -G2 variants compared with -G0 transfection. Higher levels of PGE2 and thromboxane B2, a stable metabolite of thromboxane A2, and transforming growth factor (TGF)-β1 were released into the supernatant of cultured THP-1 cells transfected with ApoL1-G1 and -G2, but not -G0. The increase in PGE2, thromboxane B2, and TGF-β1 was inhibited by COX-2-specific inhibitor CAY10404 but not by COX-1-specific inhibitor SC-560. These results demonstrate a novel role of ApoL1 variants in the regulation of monocyte differentiation and eicosanoid metabolism, which could modify the immune response and promote inflammatory signaling within the local targeted organs and tissues including the kidney.
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Shetty, Aneesha A., Ibrahim Tawhari, Luisa Safar-Boueri, Nay Seif, Ameen Alahmadi, Richard Gargiulo, Vikram Aggarwal, et al. "COVID-19–Associated Glomerular Disease." Journal of the American Society of Nephrology 32, no. 1 (November 19, 2020): 33–40. http://dx.doi.org/10.1681/asn.2020060804.
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BackgroundStudies have documented AKI with high-grade proteinuria in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In some patients, biopsies have revealed collapsing glomerulopathy, a distinct form of glomerular injury that has been associated with other viruses, including HIV. Previous patient reports have described patients of African ancestry who developed nephrotic-range proteinuria and AKI early in the course of disease.MethodsIn this patient series, we identified six patients with coronavirus disease 2019 (COVID-19), AKI, and nephrotic-range proteinuria. COVID-19 was diagnosed by a positive nasopharyngeal swab RT-PCR for SARS-CoV-2 infection. We examined biopsy specimens from one transplanted kidney and five native kidneys. Three of the six patients underwent genetic analysis of APOL1, the gene encoding the APOL1 protein, from DNA extracted from peripheral blood. In addition, we purified genomic DNA from paraffin-embedded tissue and performed APOL1 genotype analysis of one of the native biopsies and the donor kidney graft.ResultsAll six patients were of recent African ancestry. They developed COVID-19–associated AKI with podocytopathy, collapsing glomerulopathy, or both. Patients exhibited generally mild respiratory symptoms, and no patient required ventilator support. Genetic testing performed in three patients confirmed high-risk APOL1 genotypes. One APOL1 high-risk patient developed collapsing glomerulopathy in the engrafted kidney, which was transplanted from a donor who carried a low-risk APOL1 genotype; this contradicts current models of APOL1-mediated kidney injury, and suggests that intrinsic renal expression of APOL1 may not be the driver of nephrotoxicity and specifically, of podocyte injury.ConclusionsGlomerular disease presenting as proteinuria with or without AKI is an important presentation of COVID-19 infection and may be associated with a high-risk APOL1 genotype.
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Gudsoorkar, Prakash, Manish Anand, and Bassam G. Abu Jawdeh. "APOL1 Genotyping in Potential African American Living Kidney Donors: Utility and Cost-Effectiveness." American Journal of Nephrology 51, no. 2 (2020): 116–18. http://dx.doi.org/10.1159/000505719.
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Background: Apolipoprotein L1 gene (APOL1) variants predispose to nondiabetic kidney disease in African American (AA) patients. Here, we share our experience with APOL1 genotyping of AA potential living kidney donors and offer a perspective on its utility and cost-effectiveness in this population. Methods: Since May 2017, all potential AA living kidney donors at our center underwent APOL1 genotyping early in the donor evaluation process. APOL1 high-risk individuals were declined, whereas those with low-risk genotype continued with further evaluation and testing. Results: One out of 26 potential donors had high-risk genotype and was therefore declined. The rest were eligible to continue the donor evaluation process and 7 of them underwent donor nephrectomy without any complications. A crude cost analysis utilizing our sample suggested probable cost-effectiveness of APOL1 genotyping as it can prevent earlier onset of chronic kidney disease in AA donors. Conclusion: We propose a role for systematically incorporating APOL1 genotyping in the evaluation and informed consent process of potential AA donors while acknowledging the controversial considerations associated with it.
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Mishra, Abheepsa, Kamesh Ayasolla, Vinod Kumar, Xiqian Lan, Himanshu Vashistha, Rukhsana Aslam, Ali Hussain, et al. "Modulation of apolipoprotein L1-microRNA-193a axis prevents podocyte dedifferentiation in high-glucose milieu." American Journal of Physiology-Renal Physiology 314, no. 5 (May 1, 2018): F832—F843. http://dx.doi.org/10.1152/ajprenal.00541.2017.
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The loss of podocyte (PD) molecular phenotype is an important feature of diabetic podocytopathy. We hypothesized that high glucose (HG) induces dedifferentiation in differentiated podocytes (DPDs) through alterations in the apolipoprotein (APO) L1-microRNA (miR) 193a axis. HG-induced DPD dedifferentiation manifested in the form of downregulation of Wilms’ tumor 1 (WT1) and upregulation of paired box 2 (PAX2) expression. WT1-silenced DPDs displayed enhanced expression of PAX2. Immunoprecipitation of DPD cellular lysates with anti-WT1 antibody revealed formation of WT1 repressor complexes containing Polycomb group proteins, enhancer of zeste homolog 2, menin, and DNA methyltransferase (DNMT1), whereas silencing of either WT1 or DNMT1 disrupted this complex with enhanced expression of PAX2. HG-induced DPD dedifferentiation was associated with a higher expression of miR193a, whereas inhibition of miR193a prevented DPD dedifferentiation in HG milieu. HG downregulated DPD expression of APOL1. miR193a-overexpressing DPDs displayed downregulation of APOL1 and enhanced expression of dedifferentiating markers; conversely, silencing of miR193a enhanced the expression of APOL1 and preserved DPD phenotype. Moreover, stably APOL1G0-overexpressing DPDs displayed the enhanced expression of WT1 but attenuated expression of miR193a; nonetheless, silencing of APOL1 reversed these effects. Since silencing of APOL1 enhanced miR193a expression as well as dedifferentiation in DPDs, it appears that downregulation of APOL1 contributed to dedifferentiation of DPDs through enhanced miR193a expression in HG milieu. Vitamin D receptor agonist downregulated miR193a, upregulated APOL1 expression, and prevented dedifferentiation of DPDs in HG milieu. These findings suggest that modulation of the APOL1-miR193a axis carries a potential to preserve DPD molecular phenotype in HG milieu.
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Valsecchi, Manuela, Valentina Cazzetta, Ferdinando Oriolo, Xiqian Lan, Rocco Piazza, Moin A. Saleem, Pravin C. Singhal, Domenico Mavilio, Joanna Mikulak, and Massimo Aureli. "APOL1 polymorphism modulates sphingolipid profile of human podocytes." Glycoconjugate Journal 37, no. 6 (September 11, 2020): 729–44. http://dx.doi.org/10.1007/s10719-020-09944-w.
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AbstractApolipoprotein L1 (APOL1) wild type (G0) plays a role in the metabolism of sphingolipids, glycosphingolipids, sphingomyelin and ceramide, which constitute bioactive components of the lipid rafts (DRM). We asked whether APOL1 variants (APOL1-Vs) G1 and G2 carry the potential to alter the metabolism of sphingolipids in human podocytes. The sphingolipid pattern in HPs overexpressing either APOL1G0 or APOL1-Vs was analysed by using a thin mono- and bi-dimensional layer chromatography, mass-spectrometry and metabolic labelling with [1-3H]sphingosine. HP G0 and G1/G2-Vs exhibit a comparable decrease in lactosylceramide and an increase in the globotriaosylceramide content. An analysis of the main glycohydrolases activity involved in glycosphingolipid catabolism showed an overall decrease in the activeness of the tested enzymes, irrespective of the type of APOL1-Vs expression. Similarly, the high throughput cell live-based assay showed a comparable increased action of the plasma membrane glycosphingolipid-glycohydrolases in living cells independent of the genetic APOL1 expression profile. Importantly, the most significative modification of the sphingolipid pattern induced by APOL1-Vs occurred in DRM resulted with a drastic reduction of radioactivity associated with sphingolipids. G1/G2-Vs present a decrease amount of globotriaosylceramide and globopentaosylceramide compared to G0. Additionally, ceramide at the DRM site and lactosylceramide in general, showed a greatest fall in G1/G2 in comparison with G0. Additionally, the levels of glucosylceramide decreased only in the DRM of human podocytes overexpressing G1/G2-Vs. These findings suggest that altered sphingolipidsprofiles may contribute to the deranged functionality of the plasma membrane in APOL1 risk milieu.
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Reiner, Alex P., and Katalin Susztak. "APOL1 Variants." Arteriosclerosis, Thrombosis, and Vascular Biology 36, no. 2 (February 2016): 219–20. http://dx.doi.org/10.1161/atvbaha.115.306794.
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Jha, Alok, Shourav Saha, Kamesh Ayasolla, Himanshu Vashistha, Ashwani Malhotra, Karl Skorecki, and Pravin C. Singhal. "MiR193a Modulation and Podocyte Phenotype." Cells 9, no. 4 (April 17, 2020): 1004. http://dx.doi.org/10.3390/cells9041004.
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Apolipoprotein L1 (APOL1)-miR193a axis has been reported to play a role in the maintenance of podocyte homeostasis. In the present study, we analyzed transcription factors relevant to miR193a in human podocytes and their effects on podocytes’ molecular phenotype. The motif scan of the miR193a gene provided information about transcription factors, including YY1, WT1, Sox2, and VDR-RXR heterodimer, which could potentially bind to the miR193a promoter region to regulate miR193a expression. All structure models of these transcription factors and the tertiary structures of the miR193a promoter region were generated and refined using computational tools. The DNA-protein complexes of the miR193a promoter region and transcription factors were created using a docking approach. To determine the modulatory role of miR193a on APOL1 mRNA, the structural components of APOL1 3’ UTR and miR193a-5p were studied. Molecular Dynamic (MD) simulations validated interactions between miR193a and YY1/WT1/Sox2/VDR/APOL1 3′ UTR region. Undifferentiated podocytes (UPDs) displayed enhanced miR193a, YY1, and Sox2 but attenuated WT1, VDR, and APOL1 expressions, whereas differentiated podocytes (DPDs) exhibited attenuated miR193a, YY1, and Sox2 but increased WT1, VDR, APOL1 expressions. Inhibition of miR193a in UPDs enhanced the expression of APOL1 as well as of podocyte molecular markers; on the other hand, DPD-transfected with miR193a plasmid showed downing of APOL1 as well as podocyte molecular markers suggesting a causal relationship between miR193a and podocyte molecular markers. Silencing of YY1 and Sox2 in UPDs decreased the expression of miR193a but increased the expression of VDR, and CD2AP (a marker of DPDs); in contrast, silencing of WT1 and VDR in DPDs enhanced the expression of miR193a, YY1, and Sox2. Since miR193a-downing by Vitamin D receptor (VDR) agonist not only enhanced the mRNA expression of APOL1 but also of podocyte differentiating markers, suggest that down-regulation of miR193a could be used to enhance the expression of podocyte differentiating markers as a therapeutic strategy.
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Moodalbail, Divya G., and Bonita Falkner. "Apolipoprotein L1 Genetic Variants Are Associated with Evidence of Early Kidney Injury in Sickle Cell Disease." Blood 130, Suppl_1 (December 7, 2017): 985. http://dx.doi.org/10.1182/blood.v130.suppl_1.985.985.
Full textAbstract:
Abstract Background and Objectives: Apolipoprotein L1 (APOL1) renal risk variants prevalent in African-ancestry populations are associated with chronic kidney disease (CKD). CKD is a major cause of morbidity and mortality in sickle cell disease (SCD) in adults; yet the prevalence and significance of APOL1 renal-risk variants in this population remains unknown. Our objective was to determine expression of biomarkers of early kidney disease in African American youth with SCD, based on their APOL1 genotype. Methods:We enrolled65 African American subjects between 5 to 21 years of age with SCD (Hb SS or Hb S β0 thalassemia). Blood and concurrent urine samples were collected. Allenrolled subjects underwent APOL1 genotyping by PCR analysis of DNA extracted from whole blood. Presence of two renal-risk variants qualified for APOL1 High Risk (HR) genotype, while presence of zero or one copy of renal-risk variants qualified for APOL1 Low Risk (LR) genotype. Results: APOL1 HR genotype was expressed by 22% of our subjects; this is comparable to 23% prevalence of APOL1 HR genotype in African American adults with CKD (AASK study). Both groups were similar with respect to distribution of age, BMI z-scores, renal function and urine osmolality. Hyperfiltration was noted in both groups based on low serum creatinine for age, and elevated eGFR based on creatinine clearance. However, median urine albumin excretion rate was significantly higher in HR group vs. LR group. Conclusions: Preliminary data in this cohort of 65 children and adolescents with SCD detected greater urine albumin excretion rate in the presence of APOL1 HR genotype. Screening SCD youth for heightened CKD risk may be an avenue to initiate targeted preventive interventions to preserve renal function and reduce progression of kidney disease. Acknowledgment: Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number P20GM109021; National Kidney Foundation Young Investigator Grant and DE-CTR-ACCEL grant number U54-GM104941 (PI: Binder-Macleod). Disclosures No relevant conflicts of interest to declare.