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El-Dahr, Samir S., Susana Dipp, Igor V. Yosipiv y Luis A. Carbini. "Activation of kininogen expression during distal nephron differentiation". American Journal of Physiology-Renal Physiology 275, n.º 1 (1 de julio de 1998): F173—F182. http://dx.doi.org/10.1152/ajprenal.1998.275.1.f173.
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Previous studies have shown that the epithelial precursors of the connecting tubule and collecting duct express tissue kallikrein and bradykinin B2 receptors, respectively, suggesting the presence of a local kinin-producing/responsive system in the maturing distal nephron. However, evidence for the existence of kininogen in the developing nephron is still lacking. This study examined the spatiotemporal relationships between segmental nephron differentiation and the ontogeny of kininogen and kinins in the rat. Kininogen immunoreactivity is detectable in the metanephros as early as embryonic day 15. In the nephrogenic zone, the terminal ureteric bud branches are the main kinin-expressing segments. Kininogen is also observed in the stromal mesenchyme. In contrast, proximal ureteric bud branches, metanephrogenic mesenchyme, and pretubular aggregates express little or no kininogen. After completion of nephrogenesis, kininogen distribution assumes its classic “adult” pattern in the collecting ducts. Peak kininogen mRNA and protein expression occur perinatally, corresponding to the period of active nephrogenesis in the rat, and declines gradually thereafter. Estimations made by RT-PCR, Western blotting, and radioimmunoassays indicate that renal kininogen mRNA and protein levels are at least 20-fold higher in newborn than adult rats. Likewise, immunoreactive tissue kinin levels are 2.3-fold higher in newborn than adult kidneys ( P < 0.05). In summary, the present study demonstrates the activation of kininogen gene expression and kinin production in the developing kidney. The terminal ureteric bud branches and their epithelial derivatives are the principal kinin-producing segments in the maturing nephron. The results suggest an autocrine/paracrine role for the kallikrein-kinin system in distal nephron maturation.
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Chambers, Brooke E., Eleanor G. Clark, Allison E. Gatz y Rebecca A. Wingert. "Kctd15 regulates nephron segment development by repressing Tfap2a activity". Development 147, n.º 23 (7 de octubre de 2020): dev191973. http://dx.doi.org/10.1242/dev.191973.
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ABSTRACTA functional vertebrate kidney relies on structural units called nephrons, which are epithelial tubules with a sequence of segments each expressing a distinct repertoire of solute transporters. The transcriptiona`l codes driving regional specification, solute transporter program activation and terminal differentiation of segment populations remain poorly understood. Here, we demonstrate that the KCTD15 paralogs kctd15a and kctd15b function in concert to restrict distal early (DE)/thick ascending limb (TAL) segment lineage assignment in the developing zebrafish pronephros by repressing Tfap2a activity. During renal ontogeny, expression of these factors colocalized with tfap2a in distal tubule precursors. kctd15a/b loss primed nephron cells to adopt distal fates by driving slc12a1, kcnj1a.1 and stc1 expression. These phenotypes were the result of Tfap2a hyperactivity, where kctd15a/b-deficient embryos exhibited increased abundance of this transcription factor. Interestingly, tfap2a reciprocally promoted kctd15a and kctd15b transcription, unveiling a circuit of autoregulation operating in nephron progenitors. Concomitant kctd15b knockdown with tfap2a overexpression further expanded the DE population. Our study reveals that a transcription factor-repressor feedback module employs tight regulation of Tfap2a and Kctd15 kinetics to control nephron segment fate choice and differentiation during kidney development.
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Parwani, Anil V., Aliya N. Husain, Jonathan I. Epstein, J. Bruce Beckwith y Pedram Argani. "Low-grade myxoid renal epithelial neoplasms with distal nephron differentiation". Human Pathology 32, n.º 5 (mayo de 2001): 506–12. http://dx.doi.org/10.1053/hupa.2001.24320.
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MATSUDA, Kazuya, Yousuke KOUSAKA, Natsuko NAGAMINE, Nobuo TSUNODA y Hiroyuki TANIYAMA. "Papillary Renal Adenoma of Distal Nephron Differentiation in a Horse". Journal of Veterinary Medical Science 69, n.º 7 (2007): 763–65. http://dx.doi.org/10.1292/jvms.69.763.
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Schmitt, Roland, David H. Ellison, Nicolette Farman, Bernard C. Rossier, Robert F. Reilly, W. Brian Reeves, Ilse Oberbäumer, Rosemarie Tapp y Sebastian Bachmann. "Developmental expression of sodium entry pathways in rat nephron". American Journal of Physiology-Renal Physiology 276, n.º 3 (1 de marzo de 1999): F367—F381. http://dx.doi.org/10.1152/ajprenal.1999.276.3.f367.
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During the past several years, sites of expression of ion transport proteins in tubules from adult kidneys have been described and correlated with functional properties. Less information is available concerning sites of expression during tubule morphogenesis, although such expression patterns may be crucial to renal development. In the current studies, patterns of renal axial differentiation were defined by mapping the expression of sodium transport pathways during nephrogenesis in the rat. Combined in situ hybridization and immunohistochemistry were used to localize the Na-Pi cotransporter type 2 (NaPi2), the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), the thiazide-sensitive Na-Cl cotransporter (NCC), the Na/Ca exchanger (NaCa), the epithelial sodium channel (rENaC), and 11β-hydroxysteroid dehydrogenase (11HSD). The onset of expression of these proteins began in post-S-shape stages. NKCC2 was initially expressed at the macula densa region and later extended into the nascent ascending limb of the loop of Henle (TAL), whereas differentiation of the proximal tubular part of the loop of Henle showed a comparatively retarded onset when probed for NaPi2. The NCC was initially found at the distal end of the nascent distal convoluted tubule (DCT) and later extended toward the junction with the TAL. After a period of changing proportions, subsegmentation of the DCT into a proximal part expressing NCC alone and a distal part expressing NCC together with NaCa was evident. Strong coexpression of rENaC and 11HSD was observed in early nascent connecting tubule (CNT) and collecting ducts and later also in the distal portion of the DCT. Ontogeny of the expression of NCC, NaCa, 11HSD, and rENaC in the late distal convolutions indicates a heterogenous origin of the CNT. These data present a detailed analysis of the relations between the anatomic differentiation of the developing renal tubule and the expression of tubular transport proteins.
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Davis, I. D., T. W. LeBien, B. J. Lindman y J. L. Platt. "Biochemical and histochemical characterization of a murine tubular antigen." Journal of the American Society of Nephrology 1, n.º 10 (abril de 1991): 1153–61. http://dx.doi.org/10.1681/asn.v1101153.
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Cellular components of the developing fetal nephron express certain cell surface antigens at discrete stages of nephron development. To further evaluate the expression of antigens by tubular epithelium, a rat monoclonal antibody (BL26) was developed against murine fetal kidney. BL26 identified a differentiation antigen expressed by epithelial cells of the ureteric bud and late S-body in developing nephrons and by endothelium, mesangium, and distal tubular epithelium in mature nephrons. The polypeptide identified by BL26 was shown to be synthesized by fetal kidney and renal adenocarcinoma cells. The polypeptide contained no detectable carbohydrate modifications but was found in two isoforms, an acylated (26,000-Da) form and a nonacylated (24,000-Da) form. The murine antigen recognized by BL26 and the human CD9 moiety, an acylated polypeptide with a tissue distribution similar to that of the BL26 antigen, comigrated in polyacrylamide gels. We speculate that expression of the BL26 antigen and CD9 reflects processes relating to the activation of epithelial cells.
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Marneros, Alexander G. "AP-2β/KCTD1 Control Distal Nephron Differentiation and Protect against Renal Fibrosis". Developmental Cell 54, n.º 3 (agosto de 2020): 348–66. http://dx.doi.org/10.1016/j.devcel.2020.05.026.
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Wesselman, Hannah M., Allison E. Gatz, Mairead R. Pfaff, Liana Arceri y Rebecca A. Wingert. "Estrogen Signaling Influences Nephron Segmentation of the Zebrafish Embryonic Kidney". Cells 12, n.º 4 (20 de febrero de 2023): 666. http://dx.doi.org/10.3390/cells12040666.
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Despite significant advances in understanding nephron segment patterning, many questions remain about the underlying genes and signaling pathways that orchestrate renal progenitor cell fate choices and regulate differentiation. In an effort to identify elusive regulators of nephron segmentation, our lab conducted a high-throughput drug screen using a bioactive chemical library and developing zebrafish, which are a conserved vertebrate model and particularly conducive to large-scale screening approaches. 17β-estradiol (E2), which is the dominant form of estrogen in vertebrates, was a particularly interesting hit from this screen. E2 has been extensively studied in the context of gonad development, but roles for E2 in nephron development were unknown. Here, we report that exogenous estrogen treatments affect distal tubule composition, namely, causing an increase in the distal early segment and a decrease in the neighboring distal late. These changes were noted early in development but were not due to changes in cell dynamics. Interestingly, exposure to the xenoestrogens ethinylestradiol and genistein yielded the same changes in distal segments. Further, upon treatment with an estrogen receptor 2 (Esr2) antagonist, PHTPP, we observed the opposite phenotypes. Similarly, genetic deficiency of the Esr2 analog, esr2b, revealed phenotypes consistent with that of PHTPP treatment. Inhibition of E2 signaling also resulted in decreased expression of essential distal transcription factors, irx3b and its target irx1a. These data suggest that estrogenic compounds are essential for distal segment fate during nephrogenesis in the zebrafish pronephros and expand our fundamental understanding of hormone function during kidney organogenesis.
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Wolf, D. C., H. E. Whiteley y J. I. Everitt. "Preneoplastic and Neoplastic Lesions of Rat Hereditary Renal Cell Tumors Express Markers of Proximal and Distal Nephron". Veterinary Pathology 32, n.º 4 (julio de 1995): 379–86. http://dx.doi.org/10.1177/030098589503200406.
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Long-Evans (Eker) rats carry a mutation that predisposes them to develop spontaneous renal cell tumors of two morphologic patterns: solid chromophilic masses or cystic lesions lined by eosinophilic cells. Previous studies have suggested that these tumors arise from the proximal tubules. In the present study, lectin-binding characteristics and cytokeratin expression of various stages of hereditary rat renal epithelial neoplasia were examined to localize the portion of the nephron from which tumors arise. Lectin-binding histochemistry has been used as a marker of cell surface glycoprotein expression, thought to be important in the differentiation of benign from malignant epithelial lesions and in the determination of their cell of origin. The presence or absence of keratin intermediate filaments in the rat nephron has been used to identify nephron segments. The polyclonal antibody to high- and low-molecular-weight cytokeratin stained the cells of the collecting ducts but not the proximal or distal tubules. Binding to the proximal tubules by the lectins Conavalia ensiformis (Con A), Dolichas biflorus, Ricinus communis (RCA-1), and Triticum vulgare and to the distal tubules by Con A, RCA-1, Arachis hypogaea (PNA) with and without neuraminidase, and the antibody for cytokeratins was demonstrated. The lectin binding and cytokeratin staining patterns of rat hereditary renal cell carcinoma, adenoma and the preneoplastic lesions of atypical tubules and hyperplasias suggest that cystic adenomas arise from the distal nephron, principally the collecting duct, whereas the solid atypical tubules, hyperplasias, and adenomas arise from the proximal nephron, principally the proximal tubule.
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Li, Jun, Jinshu Xu, Huihui Jiang, Ting Zhang, Aarthi Ramakrishnan, Li Shen y Pin-Xian Xu. "Chromatin Remodelers Interact with Eya1 and Six2 to Target Enhancers to Control Nephron Progenitor Cell Maintenance". Journal of the American Society of Nephrology 32, n.º 11 (29 de octubre de 2021): 2815–33. http://dx.doi.org/10.1681/asn.2021040525.
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BackgroundEya1 is a critical regulator of nephron progenitor cell specification and interacts with Six2 to promote NPC self-renewal. Haploinsufficiency of these genes causes kidney hypoplasia. However, how the Eya1-centered network operates remains unknown.MethodsWe engineered a 2×HA-3×Flag-Eya1 knock-in mouse line and performed coimmunoprecipitation with anti-HA or -Flag to precipitate the multitagged-Eya1 and its associated proteins. Loss-of-function, transcriptome profiling, and genome-wide binding analyses for Eya1's interacting chromatin-remodeling ATPase Brg1 were carried out. We assayed the activity of the cis-regulatory elements co-occupied by Brg1/Six2 in vivo.ResultsEya1 and Six2 interact with the Brg1-based SWI/SNF complex during kidney development. Knockout of Brg1 results in failure of metanephric mesenchyme formation and depletion of nephron progenitors, which has been linked to loss of Eya1 expression. Transcriptional profiling shows conspicuous downregulation of important regulators for nephrogenesis in Brg1-deficient cells, including Lin28, Pbx1, and Dchs1-Fat4 signaling, but upregulation of podocyte lineage, oncogenic, and cell death–inducing genes, many of which Brg1 targets. Genome-wide binding analysis identifies Brg1 occupancy to a distal enhancer of Eya1 that drives nephron progenitor–specific expression. We demonstrate that Brg1 enrichment to two distal intronic enhancers of Pbx1 and a proximal promoter region of Mycn requires Six2 activity and that these Brg1/Six2-bound enhancers govern nephron progenitor–specific expression in response to Six2 activity.ConclusionsOur results reveal an essential role for Brg1, its downstream pathways, and its interaction with Eya1-Six2 in mediating the fine balance among the self-renewal, differentiation, and survival of nephron progenitors.
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Korhonen, M., J. Ylänne, L. Laitinen y I. Virtanen. "The alpha 1-alpha 6 subunits of integrins are characteristically expressed in distinct segments of developing and adult human nephron." Journal of Cell Biology 111, n.º 3 (1 de septiembre de 1990): 1245–54. http://dx.doi.org/10.1083/jcb.111.3.1245.
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We studied the distribution of the alpha 1-alpha 6 subunits of beta 1 integrins in developing and adult human kidney using a panel of mAbs in indirect immunofluorescence microscopy. Uninduced mesenchyme displayed a diffuse immunoreactivity for only the alpha 1 integrin subunit. At the S-shaped body stage of nephron development, several of the alpha subunits were characteristically expressed in distinct fetal nephron segments, and the pattern was retained also in the adult nephron. Thus, the alpha 1 subunit was characteristically expressed in mesangial and endothelial cells, the alpha 2 in glomerular endothelium and distal tubules, the alpha 3 in podocytes, Bowman's capsule, and distal tubules, and the alpha 6 subunit basally in all tubules, and only transiently in podocytes during development. Unlike the alpha 3 and alpha 6 subunits, the alpha 2 subunit displayed an overall cell surface distribution in distal tubules. It was also distinctly expressed in glomerular endothelia during glomerulogenesis. The beta 4 subunit was expressed only in fetal collecting ducts, and hence the alpha 6 subunit seems to be complexed with the beta 1 rather than beta 4 subunit in human kidney. Of the two fibronectin receptor alpha subunits, alpha 4 and alpha 5, only the latter was expressed, confined to endothelia of developing and adult blood vessels, suggesting that these receptor complexes play a minor role during nephrogenesis. The present results suggest that distinct integrins play a role during differentiation of specific nephron segments. They also indicate that alpha 3 beta 1 and alpha 6 beta 1 integrin complexes may function as basement membrane receptors in podocytes and tubular epithelial cells.
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Leroy, Xavier, Sebastien Aubert y Bernard Gosselin. "Low-grade myxoid renal epithelial neoplasms with distal nephron differentiation: A distinct clinicopathologic entity?" Human Pathology 33, n.º 5 (mayo de 2002): 574–75. http://dx.doi.org/10.1053/hupa.2002.124010.
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Vinay, P., J. Sénécal, J. Noël, C. Chirinian, M. C. Vinay, H. Ammann, Y. Boulanger, A. Gougoux y A. Berteloot. "Basolateral glucose transport in distal segments of the dog nephron". Canadian Journal of Physiology and Pharmacology 69, n.º 7 (1 de julio de 1991): 964–77. http://dx.doi.org/10.1139/y91-146.
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The transport of glucose by canine thick ascending limbs (TAL) and inner medullary collecting ducts (IMCD) was studied using tubule suspensions and membrane vesicles. The uptake of D-[14C(U)]glucose by a suspension of intact TAL tubules was reduced largely by phloretin (Pt), moderately by phlorizin (Pz), and completely suppressed by a combination of both agents. A selective effect of Pz on the transport of [14C]α-methyl-D-glucoside, but not on 2-[3H]deoxyglucose, was also observed in TAL tubules. In contrast, glucose transport was unaffected by Pz but entirely suppressed by Pt alone in IMCD tubules. The metabolism of glucose was largely suppressed by Pt but unaffected by Pz in both types of tubules. Membrane vesicles were prepared from the red medulla and the white papilla or from TAL and IMCD tubules isolated from these tissues. Vesicle preparations from both tissues demonstrated a predominant carrier-mediated, sodium-independent, Pt- and cytochalasin B-sensitive glucose transport. Following purification of basolateral membrane on a Percoll gradient, the sodium-insensitive D-[14C(U)]glucose transport activity copurified with the activity of the basolateral marker Na+–K+ ATPase in both tissues. However, a small sodium-dependent and Pz-sensitive component of glucose transport was found in membrane vesicles prepared from the red medulla or from thick ascending limb tubules but not from the papilla nor collecting duct tubules. The kinetic analysis of the major sodium-independent processes showed that the affinity of the transporter for glucose was greater in collecting ducts (Km = 2.3 mM) than in thick ascending limbs (Km = 4.9 mM). We conclude that glucose gains access into the cells largely through a basolateral facilitated diffusion process in both segments. However a small sodium–glucose cotransport is also detected in membranes of TAL tubules. The transport of glucose presents an axial differentiation in the affinity of glucose transporters in the renal medulla, ensuring an adequate supply of glucose to the glycolytic inner medullary structures.Key words: basolateral membranes, tubules, medulla, thick ascending limbs, collecting ducts, glucose transport, phlorizin, phloretin, dog.
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Mamenko, M., O. Zaika, N. Boukelmoune, R. G. O'Neil y O. Pochynyuk. "Deciphering physiological role of the mechanosensitive TRPV4 channel in the distal nephron". American Journal of Physiology-Renal Physiology 308, n.º 4 (15 de febrero de 2015): F275—F286. http://dx.doi.org/10.1152/ajprenal.00485.2014.
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Long-standing experimental evidence suggests that epithelial cells in the renal tubule are able to sense osmotic and pressure gradients caused by alterations in ultrafiltrate flow by elevating intracellular Ca2+ concentration. These responses are viewed as critical regulators of a variety of processes ranging from transport of water and solutes to cellular growth and differentiation. A loss in the ability to sense mechanical stimuli has been implicated in numerous pathologies associated with systemic imbalance of electrolytes and to the development of polycystic kidney disease. The molecular mechanisms conferring mechanosensitive properties to epithelial tubular cells involve activation of transient receptor potential (TRP) channels, such as TRPV4, allowing direct Ca2+ influx to increase intracellular Ca2+ concentration. In this review, we critically analyze the current evidence about signaling determinants of TRPV4 activation by luminal flow in the distal nephron and discuss how dysfunction of this mechanism contributes to the progression of polycystic kidney disease. We also review the physiological relevance of TRPV4-based mechanosensitivity in controlling flow-dependent K+ secretion in the distal renal tubule.
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Bettuzzi, Saverio, Paola Strocchi, Pierpaola Davalli, Maria Marinelli, Luciana Furci y Arnaldo Corti. "Androgen responsiveness and intrarenal localization of transcripts coding for the enzymes of polyamine metabolism in the mouse". Biochemistry and Cell Biology 79, n.º 2 (1 de abril de 2001): 133–40. http://dx.doi.org/10.1139/o01-001.
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Polyamines, spermidine (SPD), and spermine (SPM) are intracellular polycations required for cell growth and differentiation. Their biosynthetic precursor, the diamine putrescine (PUT), is produced by regulatory ornithine decarboxylase (ODC). Spermidine/spermine N1-acetyltransferase (SSAT) is the ODC counterpart in the degradation pathway which retroconverts SPM and SPD into PUT. Castration of male mice for 7 days resulted in a 40% decrease of the renal levels of both SSAT and ODC transcripts. Administration of 5-α-dihydrotestosterone (DHT) to castrated mice for the last 3 days before sacrifice caused the levels of ODC and SSAT mRNAs to increase by 250% and 180%, respectively. Thus activation of the retroconversion pathway of polyamine metabolism appears to contribute towards the increase in PUT production known to be caused by androgens in the mouse kidney. In situ hybridization histochemistry experiments showed that the SSAT transcript is expressed only by the epithelial cells of the straight and convoluted distal tubules of the nephron, while the expression of the ODC transcript is confined to the epithelium of the convoluted and straight portion of the proximal tubules. The separation of the biosynthetic from the degradation pathway along the nephron suggests that PUT is mostly produced in the distal tubule, where it may play a physiological role, independent of androgen action, in protecting tubular cells from the very low osmolarity to which they are exposed in this nephron segment.Key words: Adenosylmethionine decarboxylase, spermidine/spermine N1-acetyltransferase, ornithine decarboxylase, mouse kidney, polyamines.
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Holthöfer, H. y I. Virtanen. "Glycosylation of developing human glomeruli: lectin binding sites during cell induction and maturation." Journal of Histochemistry & Cytochemistry 35, n.º 1 (enero de 1987): 33–37. http://dx.doi.org/10.1177/35.1.3794308.
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Expression of cellular glycoconjugates during differentiation of human fetal kidney was studied using fluorochrome-labeled lectins. Each lectin revealed a characteristic binding pattern during the phenotypic change of the nephrogenic mesenchyme and during distinct stages of nephron development. The uninduced mesenchymal cells were positive for Pisum sativum (PSA), Concanavalin A (ConA), Wistaria floribunda (WGA), and Ricinus communis (RCA-I) lectins. However, these lectins failed to react with the uninduced cells of the S-shaped bodies, whereas Maclura pomifera (MPA), Triticum vulgaris (WGA) and, after neuraminidase treatment, Arachis hypogaea (PNA) agglutinins bound intensely to the presumptive podocytes. During later stages of nephrogenesis, MPA positively on the podocytes weakened and could not be observed in adult kidney glomeruli. Binding sites for Helix pomatia (HPA) agglutinin in glomeruli were also expressed only transiently during nephrogenesis. During further development PSA, ConA, WFA, and RCA-I reacted with mesangial cells in addition to the glomerular basement membranes. The segment-specific lectin binding patterns of the tubuli emerged in parallel with the appearance of brush border and Tamm-Horsfall antigens of the proximal and distal tubuli. The results show that nephron site-specific saccharides appear in a developmentally regulated manner and in parallel with morphologic maturation of the nephron. Lectins therefore appear to be useful tools for study of induction and maturation of various nephron cell types.
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Bomhard, E., D. Maruhn, O. Vogel y H. Mager. "Determination of urinary glutathione S-transferase and lactate dehydrogenase for differentiation between proximal and distal nephron damage". Archives of Toxicology 64, n.º 4 (junio de 1990): 269–78. http://dx.doi.org/10.1007/bf01972986.
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ZEHNDER, DANIEL, ROSEMARY BLAND, ELIZABETH A. WALKER, ARTHUR R. BRADWELL, ALEXANDER J. HOWIE, MARTIN HEWISON y PAUL M. STEWART. "Expression of 25-Hydroxyvitamin D3-1α-Hydroxylase in the Human Kidney". Journal of the American Society of Nephrology 10, n.º 12 (diciembre de 1999): 2465–73. http://dx.doi.org/10.1681/asn.v10122465.
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Abstract. The secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plays a vital role in calcium metabolism, tissue differentiation, and normal bone growth. Biosynthesis of 1,25(OH)2D3 is catalyzed by the mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin D3 1α-hydroxylase (1α-hydroxylase). Although activity of this enzyme has been described in several tissues, the kidneys are recognized to be the principal site of 1,25(OH)2D3 production. To date, enzyme activity studies using vitamin D-deficient animals have suggested that 1α-hydroxylase is expressed exclusively in proximal convoluted tubules. With the recent cloning of 1α-hydroxylase, specific cRNA probes and in-house polyclonal antiserum have been used to determine the distribution of 1α-hydroxylase along the human nephron. Immunohistochemistry and in situ hybridization studies indicated strong expression of 1α-hydroxylase protein and mRNA in the distal convoluted tubule, the cortical and medullary part of the collecting ducts, and the papillary epithelia. Lower expression was observed along the thick ascending limb of the loop of Henle and Bowman's capsule. Weaker and more variable expression of 1α-hydroxylase protein and mRNA was seen in proximal convoluted tubules, and no expression was observed in glomeruli or vascular structures. These data show for the first time the distribution of 1α-hydroxylase expression in normal human kidney. In contrast to earlier enzyme activity studies conducted in vitamin D-deficient animals, our data indicate that the distal nephron is the predominant site of 1α-hydroxylase expression under conditions of vitamin D sufficiency.
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Vanslambrouck, Jessica M., Sean B. Wilson, Ker Sin Tan, Joanne Y. C. Soo, Michelle Scurr, H. Siebe Spijker, Lakshi T. Starks et al. "A Toolbox to Characterize Human Induced Pluripotent Stem Cell–Derived Kidney Cell Types and Organoids". Journal of the American Society of Nephrology 30, n.º 10 (6 de septiembre de 2019): 1811–23. http://dx.doi.org/10.1681/asn.2019030303.
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BackgroundThe generation of reporter lines for cell identity, lineage, and physiologic state has provided a powerful tool in advancing the dissection of mouse kidney morphogenesis at a molecular level. Although use of this approach is not an option for studying human development in vivo, its application in human induced pluripotent stem cells (iPSCs) is now feasible.MethodsWe used CRISPR/Cas9 gene editing to generate ten fluorescence reporter iPSC lines designed to identify nephron progenitors, podocytes, proximal and distal nephron, and ureteric epithelium. Directed differentiation to kidney organoids was performed according to published protocols. Using immunofluorescence and live confocal microscopy, flow cytometry, and cell sorting techniques, we investigated organoid patterning and reporter expression characteristics.ResultsEach iPSC reporter line formed well patterned kidney organoids. All reporter lines showed congruence of endogenous gene and protein expression, enabling isolation and characterization of kidney cell types of interest. We also demonstrated successful application of reporter lines for time-lapse imaging and mouse transplantation experiments.ConclusionsWe generated, validated, and applied a suite of fluorescence iPSC reporter lines for the study of morphogenesis within human kidney organoids. This fluorescent iPSC reporter toolbox enables the visualization and isolation of key populations in forming kidney organoids, facilitating a range of applications, including cellular isolation, time-lapse imaging, protocol optimization, and lineage-tracing approaches. These tools offer promise for enhancing our understanding of this model system and its correspondence with human kidney morphogenesis.
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Gerges, Daniela, Zsofia Hevesi, Sophie H. Schmidt, Sebastian Kapps, Sahra Pajenda, Barbara Geist, Alice Schmidt, Ludwig Wagner y Wolfgang Winnicki. "Tubular epithelial progenitors are excreted in urine during recovery from severe acute kidney injury and are able to expand and differentiate in vitro". PeerJ 10 (20 de octubre de 2022): e14110. http://dx.doi.org/10.7717/peerj.14110.
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Background Acute kidney injury (AKI) is a serious condition associated with chronic kidney disease, dialysis requirement and a high risk of death. However, there are specialized repair mechanisms for the nephron, and migrated committed progenitor cells are the key players. Previous work has described a positive association between renal recovery and the excretion of tubular progenitor cells in the urine of kidney transplant recipients. The aim of this work was to describe such structures in non-transplanted AKI patients and to focus on their differentiation. Methods Morning urine was obtained from four patients with AKI stage 3 and need for RRT on a consecutive basis. Urine sediment gene expression was performed to assess which part of the tubular or glomerular segment was affected by injury, along with measurement of neprilysin. Urine output and sediment morphology were monitored, viable hyperplastic tubular epithelial clusters were isolated and characterized by antibody or cultured in vitro. These cells were monitored by phase contrast microscopy, gene, and protein expression over 9 days by qPCR and confocal immunofluorescence. Furthermore, UMOD secretion into the supernatant was quantitatively measured. Results Urinary neprilysin decreased rapidly with increasing urinary volume in ischemic, toxic, nephritic, and infection-associated AKI, whereas the decrease in sCr required at least 2 weeks. While urine output increased, dead cells were present in the sediment along with debris followed by hyperplastic agglomerates. Monitoring of urine sediment for tubular cell-specific gene transcript levels NPHS2 (podocyte), AQP1 and AQP6 (proximal tubule), and SLC12A1 (distal tubule) by qPCR revealed different components depending on the cause of AKI. Confocal immunofluorescence staining confirmed the presence of intact nephron-specific epithelial cells, some of which appeared in clusters expressing AQP1 and PAX8 and were 53% positive for the stem cell marker PROM1. Isolated tubule epithelial progenitor cells were grown in vitro, expanded, and reached confluence within 5–7 days, while the expression of AQP1 and UMOD increased, whereas PROM1 and Ki67 decreased. This was accompanied by a change in cell morphology from a disproportionately high nuclear/cytoplasmic ratio at day 2–7 with mitotic figures. In contrast, an apoptotic morphology of approximately 30% was found at day 9 with the appearance of multinucleated cells that were associable with different regions of the nephron tubule by marker proteins. At the same time, UMOD was detected in the culture supernatant. Conclusion During renal recovery, a high replicatory potential of tubular epithelial progenitor cells is found in urine. In vitro expansion and gene expression show differentiation into tubular cells with marker proteins specific for different nephron regions.
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Singer, Pamela, Christine B. Sethna, Laura Castellanos-Reyes, Oksana Yaskiv y Vanesa Bijol. "Kidney Biopsy Findings in a Patient With Valproic Acid-Associated Fanconi Syndrome". Pediatric and Developmental Pathology 22, n.º 4 (19 de diciembre de 2018): 370–74. http://dx.doi.org/10.1177/1093526618819334.
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A 7-year-old boy with a history of febrile illness-related epilepsy syndrome presented with proteinuria and elevated creatinine. His severe epileptic disorder has been treated since age 2 with multiple antiepileptic medications, including valproic acid. More recently, he was noted to have features of Fanconi syndrome with acidosis, hypophosphatemia, hypokalemia, glucosuria, and nephrotic-range proteinuria. This was managed with supplements; however, in the setting of rising creatinine and prominent proteinuria, a kidney biopsy was performed. Renal cortex revealed markedly decreased expression of proximal tubule markers and increased expression of markers of distal nephron differentiation. Such findings have been described in several genetic and acquired conditions, including renal tubular dysgenesis, severe hypoxic injury following renal artery stenosis, and toxic injury related to in utero exposure to angiotensin-converting-enzyme inhibitors. Such changes have not been reported before in valproic acid-associated Fanconi syndrome, although in general, morphologic findings in this condition have not been well established in the literature.
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Bhat, Pangala V., Mieczyslaw Marcinkiewicz, Yuan Li y Sylvie Mader. "Changing Patterns of Renal Retinal Dehydrogenase Expression Parallel Nephron Development in the Rat". Journal of Histochemistry & Cytochemistry 46, n.º 9 (septiembre de 1998): 1025–32. http://dx.doi.org/10.1177/002215549804600906.
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We have recently characterized a cytosolic aldehyde dehydrogenase from rat kidney that functions as a retinal dehydrogenase (RALDH) and have cloned the corresponding gene. RALDH catalyzes the oxidation of retinal to retinoic acid, which regulates cell growth and differentiation by activating retinoic acid receptors. In situ hybridization demonstrates that RALDH mRNA expression is prominent in kidney in 2-day-old rats, is detected in lung and in epithelia of several tissues, but is not found in liver tissue. Retinal dehydrogenase activity peaks in kidney at Day 2 after birth and decreases gradually until adulthood, correlating well with RALDH expression. Weaker activity is also detectable in lungs but not in liver. Notably, distribution patterns of RALDH in kidney tissues are dramatically altered during postnatal development (P). From P0 to P6, hybridization is essentially concentrated within the marginal nephrogenic zone of the cortex. Expression progresses to deeper cortical layers from P12 to P16 and is intense in the medulla at P42, and focal expression is still detectable in the cortex. Immunocytochemical localization of RALDH in neonatal kidney shows staining mostly in cortical zone convoluted tubules and in adult rat shows staining in segments of distal and proximal tubules. These data suggest an important role for RALDH in modulating retinoic acid levels in different cell types during rat kidney development. The changing patterns of RALDH expression mirror stages of nephron formation in the developing rat kidney, strongly suggesting a central role for RALDH and thus for retinoids in controlling kidney development.
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Ramasubbu, K., N. Gretz y S. Bachmann. "Increased epithelial cell proliferation and abnormal extracellular matrix in rat polycystic kidney disease." Journal of the American Society of Nephrology 9, n.º 6 (junio de 1998): 937–45. http://dx.doi.org/10.1681/asn.v96937.
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Proliferation of renal tubular epithelial cells is considered a major factor leading to cyst formation in human polycystic kidney disease (PKD). The Han:SPRD rat model for inherited PKD permits a close scrutiny, especially for early stages of the disease, and shows numerous similarities to human autosomal dominant PKD (ADPKD). In this study, the exact in vivo proliferation rate in Han:SPRD rat kidneys was evaluated in a cell type-specific manner, using immunohistochemistry with antibody to proliferating cell nuclear antigen (PCNA). The proliferation index (PI; percentage of PCNA-positive cell nuclei) was determined in normal and cystically altered tissue, and a relationship between proliferative activity and alterations in extracellular matrix expression was established using in situ hybridization for collagen I and IV mRNA. Heterozygously affected rats (cy/+) showed strong increases of PI values in cystically altered nephron portions that were mostly derived from proximal tubule. Cell proliferation obviously preceded cyst formation, because early in the progression of the disease, the normal-appearing tubules from PKD kidneys had markedly increased PI values compared with healthy controls (14.1-fold in 3-mo-old rats and 11.9-fold in 12-mo-old rats; P < 0.05), whereas later stages revealed a more generalized cystic degeneration of the nephron, with increases in PI between 14- and 82-fold, depending on the respective category of cystic epithelia. In cysts with a distal phenotype, changes were less pronounced. No significant differences were encountered between the two age groups. Proliferation was also present in interstitial cells, whereas glomeruli were unchanged. Increases in epithelial and interstitial proliferation coincided with an overexpression of matrix compounds. For comparison, changes in homozygously affected rats (cy/cy) showed up to several hundred-fold elevated PI values. These results indicate that in the Han:SPRD model for ADPKD, cystic malformation of the nephron is preceded by and coincides with enhanced epithelial and interstitial cell proliferation. Altered cell-matrix interactions seem to be directly involved in the disruption of epithelial differentiation.
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Rogers, Sharon A. y Marc R. Hammerman. "Transplantation of metanephroi after preservation in vitro". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, n.º 2 (1 de agosto de 2001): R661—R665. http://dx.doi.org/10.1152/ajpregu.2001.281.2.r661.
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To determine whether transplanted metanephroi grow, differentiate, and function in hosts after preservation in vitro, we implanted metanephroi from embryonic day 15 ( E15) Sprague-Dawley rat embryos into the omentum of nonimmunosuppressed uninephrectomized Sprague-Dawley (host) rats. Metanephroi were either implanted directly or suspended in ice-cold University of Wisconsin (UW) preservation solution with or without added growth factors for 3 days before implantation. The size and extent of tissue differentiation preimplantation of E15 metanephroi implanted directly were not distinguishable from the size and differentiation of metanephroi preserved for 3 days. In contrast, E16 metanephroi were larger than E15 metanephroi preserved for 3 days. E16 metanephroi or E13 metanephroi grown in organ culture for 3 days contained more differentiated nephron structures than those in E15 metanephroi preserved for 3 days. By 4 wk posttransplantation, metanephroi that had been preserved for 3 days had grown and differentiated such that glomeruli, proximal and distal tubules, and collecting ducts with normal structure had developed. At 12 wk posttransplantation, inulin clearances of preserved metanephroi were comparable to those of metanephroi that had been implanted directly. Addition of growth factors to the UW solution enhanced inulin clearances. Here we show for the first time that functional kidneys develop from metanephroi transplanted from rat embryos to adult rats after as long as 3 days of preservation in vitro.
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Kanwar, Yashpal S., Jun Wada, Sun Lin, Farhad R. Danesh, Sumant S. Chugh, Qiwei Yang, Tushar Banerjee y Jon W. Lomasney. "Update of extracellular matrix, its receptors, and cell adhesion molecules in mammalian nephrogenesis". American Journal of Physiology-Renal Physiology 286, n.º 2 (febrero de 2004): F202—F215. http://dx.doi.org/10.1152/ajprenal.00157.2003.
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One of the hallmarks of mammalian nephrogenesis includes a mesenchymal-epithelial transition that is accomplished by intercalation of the ureteric bud, an epithelium-lined tubelike structure, into an undifferentiated mesenchyme, and the latter then undergoes an inductive transformation and differentiates into an epithelial phenotype. At the same time, the differentiating mesenchyme reciprocates by inducing branching morphogenesis of the ureteric bud, which forms a treelike structure with dichotomous iterations. These reciprocal inductive interactions lead to the development of a functioning nephron unit made up of a glomerulus and proximal and distal tubules. The inductive interactions and differentiation events are modulated by a number of transcription factors, protooncogenes, and growth factors and their receptors, which regulate the expression of target morphogenetic modulators including the ECM, integrin receptors, and cell adhesion molecules. These target macromolecules exhibit spatiotemporal and stage-specific developmental regulation in the metanephros. The ECM molecules expressed at the epithelial-mesenchymal interface are perhaps the most relevant and conducive to the paracrine-juxtacrine interactions in a scenario where the ligand is expressed in the mesenchyme while the receptor is located in the ureteric bud epithelium or vice versa. In addition, expression of the target ECM macromolecules is regulated by matrix metalloproteinases and their inhibitors to generate a concentration gradient at the interface to further propel epithelial-mesenchymal interactions so that nephrogenesis can proceed seamlessly. In this review, we discuss and update our current understanding of the role of the ECM and related macromolecules with respect to metanephric development.
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Yousef Yengej, Fjodor A., Jitske Jansen, Maarten B. Rookmaaker, Marianne C. Verhaar y Hans Clevers. "Kidney Organoids and Tubuloids". Cells 9, n.º 6 (26 de mayo de 2020): 1326. http://dx.doi.org/10.3390/cells9061326.
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In the past five years, pluripotent stem cell (PSC)-derived kidney organoids and adult stem or progenitor cell (ASC)-based kidney tubuloids have emerged as advanced in vitro models of kidney development, physiology, and disease. PSC-derived organoids mimic nephrogenesis. After differentiation towards the kidney precursor tissues ureteric bud and metanephric mesenchyme, their reciprocal interaction causes self-organization and patterning in vitro to generate nephron structures that resemble the fetal kidney. ASC tubuloids on the other hand recapitulate renewal and repair in the adult kidney tubule and give rise to long-term expandable and genetically stable cultures that consist of adult proximal tubule, loop of Henle, distal tubule, and collecting duct epithelium. Both organoid types hold great potential for: (1) studies of kidney physiology, (2) disease modeling, (3) high-throughput screening for drug efficacy and toxicity, and (4) regenerative medicine. Currently, organoids and tubuloids are successfully used to model hereditary, infectious, toxic, metabolic, and malignant kidney diseases and to screen for effective therapies. Furthermore, a tumor tubuloid biobank was established, which allows studies of pathogenic mutations and novel drug targets in a large group of patients. In this review, we discuss the nature of kidney organoids and tubuloids and their current and future applications in science and medicine.
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Nadasdy, T., G. Lajoie, Z. Laszik, K. E. Blick, G. Molnar-Nadasdy y F. G. Silva. "Cell Proliferation in the Developing Human Kidney". Pediatric and Developmental Pathology 1, n.º 1 (enero de 1998): 49–55. http://dx.doi.org/10.1007/s100249900006.
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In a previous study, utilizing antibodies to proliferating cell nuclear antigen (PCNA), we determined the proliferation index (PI) (percentage of PCNA-positive cells) of intrinsic renal cell populations in the normal adult and pediatric kidney. We have found that the PI in both adult and pediatric kidneys was very low (below 0.5 in all examined cell populations). In our present study, we investigated cell proliferation in the developing human kidney with an antibody to PCNA. Histologically normal kidneys were collected from 25 fetuses (spontaneous abortions and stillborns) ranging from 10 wk of gestation to term. Immature mesenchyme (blastema), immature early tubules, ampulla of ureteric bud, proximal tubules, Tamm-Horsfall protein (THP)-positive tubules, distal tubules, collecting ducts, and glomeruli were evaluated separately. The PI for each cell population was calculated. The PI of immature early tubules remains high (33–43) throughout embryonic life. The PI of blastemal cells is initially similarly high, but gradually decreases starting from the second trimester. The PI of THP-positive tubules, distal tubules, collecting ducts, and glomeruli starts out relatively high (5.9, 8.6, 6.0, and 12.4, respectively) and decreases gradually as term approaches (1.8, 1.3, 1.2, and 1.4, respectively). Interestingly, as soon as proximal tubules become differentiated (appearance of light microscopic features of proximal tubular epithelium with TP lectin positive brush border), their PI becomes very low (below 1) irrespective of the age of the kidney. This is the first quantitative study to show changes of the PI in various renal cell populations during human nephrogenesis. These changes in the PI relate to the stage of differentiation of the developing nephron segments.
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EVERETT, ALLEN D., CHUN XUE y TAMARA STOOPS. "Developmental Expression of Protein Phosphatase 2A in the Kidney". Journal of the American Society of Nephrology 10, n.º 8 (agosto de 1999): 1737–45. http://dx.doi.org/10.1681/asn.v1081737.
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Abstract. Although a number of growth and transcription factors are known to regulate renal growth and development, the signal transduction molecules necessary to mediate these developmental signals are relatively unknown. Therefore, the activity and mRNA and protein expression of the signal transduction molecule protein phosphatase 2A (PP2A) were examined during rat kidney development. Northern analysis of total kidney RNA or Western analysis of kidney protein homogenates from embryonic day 15 to 90-d-old adults demonstrated developmental regulation of the catalytic, major 55-kD B regulatory subunit and A structural subunit with the highest levels of expression in late embryonic and newborn kidneys. Similarly, okadaic acid-inhibitable phosphatase enzyme activity was highest in the embryonic and newborn kidney. To map cell-specific expression of PP2A in the developing kidney, in situ hybridization with a catalytic subunit digoxigenin-labeled cRNA was performed on embryonic day 20 and newborn kidneys. PP2A was found predominately in the nephrogenic cortex and particularly in the developing glomeruli and nonbrush border tubules in the embryonic day 20 and newborn kidneys. Similarly, immunocytochemistry with a specific PP2A catalytic subunit polyclonal anti-peptide antibody demonstrated catalytic subunit protein particularly concentrated in the podocytes of glomeruli in the newborn kidney. In the adult kidney, PP2A protein was no longer detectable except in the nuclei of distal tubular cells. Therefore, the developmental regulation of PP2A activity and protein during kidney development and its mapping to the nephrogenic cortex, developing glomeruli, and tubules suggests a role for PP2A in the regulation of nephron growth and differentiation.
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Jeličić, Ivo, Katarina Vukojević, Anita Racetin, Davor Čarić, Merica Glavina Durdov, Mirna Saraga-Babić y Natalija Filipović. "Expression of Pannexin 1 in the Human Kidney during Embryonal, Early Fetal and Postnatal Development and Its Prognostic Significance in Diabetic Nephropathy". Biomedicines 10, n.º 5 (20 de abril de 2022): 944. http://dx.doi.org/10.3390/biomedicines10050944.
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Pannexins are transmembrane glycoproteins that constitute channels involved in purinergic signaling through ATP release from cells in various physiological and pathological processes. In this study, the distribution of Panx1 expression in different cell populations of healthy postnatal human kidneys and during human embryonic and early fetal development was investigated by double immunohistochemistry. In addition, the glomerular and tubular expression of Panx1 was examined in patients with type 2 diabetes mellitus (DM2) and the control group, and renal Panx1 expression was correlated with serum creatinine. In the 6th week of embryonic development (DW), Panx1 expression was found in mesonephric glomeruli and mesonephric tubules. At the transition from 6th to 7th DW, Panx1 immunoreactivity was found in the mesonephric tubules and mesonephric duct, as well as in the metanephric ureteric bud and ampullae. In the 7th DW, strong Panx1 immunoreactivity was observed in the developing ureteric bud in the metanephros, whereas no Panx1 immunoreactivity was found in the metanephric cup. In the 8th DW, Panx1 expression was also found in the ureteric bud of the metanephros, the renal vesicle and comma-shaped nephron, and the epithelial cells of Bowman’s capsule. Expression of Panx1 was found at an early stage in both the paramesonephric duct and the mesonephric duct and diminished toward the 8th DW. During the 6th–10th DW, colocalization of Panx1 with alpha smooth actin (aSMA) was found in developing blood vessels. In the postnatal kidney, strong Panx1 immunoreactivity was present in medullary and cortical collecting duct cells, renin-producing cells, and proximal tubules. Very weak Panx1 immunoreactivity was found in certain distal tubule cells and the thin descending limbs of the loop of Henle. Panx1 immunoreactivity was also found in nephrin-immunoreactive podocytes. Panx1 was not colocalized with aSMA immunoreactivity in the vessels of the postnatal human kidney, but it was present in the endothelium. A significant positive correlation was found between Panx1 expression in glomeruli and serum creatinine only in diabetic patients and was not found in the nondiabetic group. The spatiotemporal expression of Panx1 during the early stages of human kidney development supports its possible role in cellular differentiation, migration, and positioning in the developing human kidney. In addition, our data suggest that glomerular Panx1 expression is a potential indicator of worsening renal function in patients with type 2 diabetes.
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Lee, David B. N., Edmund Huang y Harry J. Ward. "Tight junction biology and kidney dysfunction". American Journal of Physiology-Renal Physiology 290, n.º 1 (enero de 2006): F20—F34. http://dx.doi.org/10.1152/ajprenal.00052.2005.
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The epithelial tight junction (TJ) has three major functions. As a “gate,” it serves as a regulatory barrier separating and maintaining biological fluid compartments of different composition. As a “fence,” it generates and maintains the apicobasal polarity of cells that form the confluent epithelium. Finally, the TJ proteins form a trafficking and signaling platform that regulates cell growth, proliferation, differentiation, and dedifferentiation. Six examples are selected that illustrate the emerging link between TJ dysfunction and kidney disease. First, the glomerular slit diaphragm (GSD) is evolved, in part, from the TJ and, on maturation, exhibits all three functions of the TJ. GSD dysfunction leads to proteinuria and, in some instances, podocyte dedifferentiation and proliferation. Second, accumulating evidence supports epithelial-mesenchymal transformation (EMT) as a major player in renal fibrosis, the final common pathway that leads to end-stage renal failure. EMT is characterized by a loss of cell-cell contact and apicobasal polarity, which are hallmarks of TJ dysfunction. Third, in autosomal dominant polycystic kidney disease, mutations of the polycystins may disrupt their known interactions with the apical junction complex, of which the TJ is a major component. This can lead to disturbances in epithelial polarity regulation with consequent abnormal tubulogenesis and cyst formation. Fourth, evidence for epithelial barrier and polarity dysregulation in the pathogenesis of ischemic acute renal failure will be summarized. Fifth, the association between mutations of paracellin-1, the first TJ channel identified, and clinical disorders of magnesium and calcium wasting and bovine renal fibrosis will be used to highlight an integral TJ protein that can serve multiple TJ functions. Finally, the role of WNK4 protein kinase in shunting chloride across the TJ of the distal nephron will be addressed.
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Oosterwijk, E., G. N. Van Muijen, J. C. Oosterwijk-Wakka y S. O. Warnaar. "Expression of intermediate-sized filaments in developing and adult human kidney and in renal cell carcinoma." Journal of Histochemistry & Cytochemistry 38, n.º 3 (marzo de 1990): 385–92. http://dx.doi.org/10.1177/38.3.1689337.
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We studied the distribution of intermediate-sized filaments in developing and adult kidneys and renal cell carcinoma (RCC) by indirect immunohistochemistry, using a pan-cytokeratin mouse monoclonal antibody (MAb), chain-specific anti-cytokeratin MAb, and anti-vimentin and anti-desmin MAb, to resolve controversy concerning intermediate-sized filament expression in the kidney. With the pan-cytokeratin MAb, cytokeratin expression was detectable in all stages of nephron development, starting with expression in the renal vesicles, the progenitors of the glomeruli, proximal tubules, Henle's loop, and part of the distal tubules. Using chain-specific anti-cytokeratin MAb, cytokeratin 8 and 18 expression was demonstrated in all developmental structures of the nephron, whereas cytokeratin 19 expression was more complex. None of the nephrogenic blastema cells from which the renal vesicles arise expressed cytokeratins. Transient expression of vimentin and cytokeratin 19 was observed in differentiating collecting ducts and proximal tubule cells at the S-shaped stage of nephron development, respectively. In RCC, cytokeratin expression closely resembled that of the mature proximal tubule, i.e., RCC cells expressed cytokeratins 8 and 18. However, in a subset of RCC additional cytokeratin 19 expression was noted. In addition, all except one RCC showed co-expression of cytokeratins and vimentin.
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Mukhopadhyay, Sanjay, Alfredo Luis Valente y Gustavo de la Roza. "Cystic Nephroma: A Histologic and Immunohistochemical Study of 10 Cases". Archives of Pathology & Laboratory Medicine 128, n.º 12 (1 de diciembre de 2004): 1404–11. http://dx.doi.org/10.5858/2004-128-1404-cnahai.
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Abstract Context.—Cystic nephroma is a rare and controversial benign multicystic renal tumor. While the clinical, radiologic, and histologic features of cystic nephroma are well described, the immunohistochemical features are not. The role of immunohistochemistry in the differential diagnosis, which includes multicystic renal cell carcinoma, is also unknown. Objective.—To define the histologic and immunohistochemical features of cystic nephroma. Design.—Ten cases of cystic nephroma diagnosed at 2 institutions during a period of 10 years were stained with an immunohistochemical panel consisting of 20 immunostains. Results.—Median age at diagnosis was 61 years, with a range from 31 to 79 years. The female-to-male ratio was 9:1. Grossly, the tumors were multicystic masses without solid nodules. Histologic features included cysts lined by flat, cuboidal, or hobnail epithelium and septa variably lined by fibrous (10/10 cases) and/or ovarian-like (7/10 cases) stroma. Corpus albicans–like acellular hyalinized structures were noted in the septa in 9 of 10 cases. The cyst epithelium showed consistent positivity for distal tubule/collecting duct markers (cytokeratin 19, cytokeratin AE1/AE3, epithelial membrane antigen) and variable positivity for proximal tubule markers (α1-antitrypsin, lysozyme, CD15, CD10). The ovarian-like stroma (present in 7/10 cases) stained positively for progesterone receptors (6/7 cases) and estrogen receptors (4/7 cases). Conclusions.—Our immunohistochemical findings confirm a previous report of both distal tubule/collecting duct and proximal tubule differentiation in cystic nephroma. Stromal estrogen and/or progesterone receptor positivity in the majority of cases of cystic nephroma is a novel finding.
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Ilatovskaya, Daria V., Vladislav Levchenko, Michael W. Brands, Tengis S. Pavlov y Alexander Staruschenko. "Cross-talk between insulin and IGF-1 receptors in the cortical collecting duct principal cells: implication for ENaC-mediated Na+ reabsorption". American Journal of Physiology-Renal Physiology 308, n.º 7 (1 de abril de 2015): F713—F719. http://dx.doi.org/10.1152/ajprenal.00081.2014.
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Insulin and IGF-1 are recognized as powerful regulators of the epithelial Na+ channel (ENaC) in the aldosterone-sensitive distal nephron. As previously described, these hormones both acutely increase ENaC activity in freshly isolated split open tubules and cultured principal cortical collecting duct cells. The present study was aimed at differentiating the effects of insulin and IGF-1 on Na+ transport in immortalized mpkCCDcl4 cells and defining their interrelations. We have shown that both insulin and IGF-1 applied basolaterally, but not apically, enhanced transepithelial Na+ transport in the mpkCCDcl4 cell line with EC50 values of 8.8 and 14.5 nM, respectively. Insulin treatment evoked phosphorylation of both insulin and IGF-1 receptors, whereas the effects of IGF-1 were more profound on its own receptor rather than the insulin receptor. AG-1024 and PPP, inhibitors of IGF-1 and insulin receptor tyrosine kinase activity, diminished insulin- and IGF-1-stimulated Na+ transport in mpkCCDcl4 cells. The effects of insulin and IGF-1 on ENaC-mediated currents were found to be additive, with insulin likely stimulating both IGF-1 and insulin receptors. We hypothesize that insulin activates IGF-1 receptors in addition to its own receptors, making the effects of these hormones interconnected.
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Nguyen, Lisa, Lucas-Sebastian Spitzhorn y James Adjaye. "Constructing an Isogenic 3D Human Nephrogenic Progenitor Cell Model Composed of Endothelial, Mesenchymal, and SIX2-Positive Renal Progenitor Cells". Stem Cells International 2019 (2 de mayo de 2019): 1–11. http://dx.doi.org/10.1155/2019/3298432.
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Urine has become the source of choice for noninvasive renal epithelial cells and renal stem cells which can be used for generating induced pluripotent stem cells. The aim of this study was to generate a 3D nephrogenic progenitor cell model composed of three distinct cell types—urine-derived SIX2-positive renal progenitor cells, iPSC-derived mesenchymal stem cells, and iPSC-derived endothelial cells originating from the same individual. Characterization of the generated mesenchymal stem cells revealed plastic adherent growth and a trilineage differentiation potential to adipocytes, chondrocytes, and osteoblasts. Furthermore, these cells express the typical MSC markers CD73, CD90, and CD105. The induced endothelial cells express the endothelial cell surface marker CD31. Upon combination of urine-derived renal progenitor cells, induced mesenchymal stem cells, and induced endothelial cells at a set ratio, the cells self-condensed into three-dimensional nephrogenic progenitor cells which we refer to as 3D-NPCs. Immunofluorescence-based stainings of sectioned 3D-NPCs revealed cells expressing the renal progenitor cell markers (SIX2 and PAX8), podocyte markers (Nephrin and Podocin), the endothelial marker (CD31), and mesenchymal markers (Vimentin and PDGFR-β). These 3D-NPCs share kidney progenitor characteristics and thus the potential to differentiate into podocytes and proximal and distal tubules. As urine-derived renal progenitor cells can be easily obtained from cells shed into urine, the generation of 3D-NPCs directly from renal progenitor cells instead of pluripotent stem cells or kidney biopsies holds a great potential for the use in nephrotoxicity tests, drug screening, modelling nephrogenesis and diseases.
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Sawai, Kazutomo, Masashi Mukoyama, Kiyoshi Mori, Masato Kasahara, Masao Koshikawa, Hideki Yokoi, Tetsuro Yoshioka et al. "Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney". American Journal of Physiology-Renal Physiology 293, n.º 4 (octubre de 2007): F1363—F1372. http://dx.doi.org/10.1152/ajprenal.00205.2007.
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CCN1 (cysteine-rich protein 61; Cyr61) is an extracellular matrix-associated signaling molecule that functions in cell migration, adhesion, and differentiation. We previously reported that CCN1 is induced at podocytes in rat anti-Thy-1 glomerulonephritis, a well-known model of reversible glomerular injury, but its expression and significance in the human kidney remain totally unknown (Sawai K, Mori K, Mukoyama M, Sugawara A, Suganami T, Koshikawa M, Yahata K, Makino H, Nagae T, Fujinaga Y, Yokoi H, Yoshioka T, Yoshimoto A, Tanaka I, Nakao K. J Am Soc Nephrol 14: 1154–1163, 2003). Here we report that, in the human kidney, CCN1 expression was confined to podocytes in normal adult and embryonic glomeruli from the capillary loop stage. Podocyte CCN1 expression was decreased in IgA nephropathy, diabetic nephropathy, and membranous nephropathy, whereas it remained unchanged in minimal change disease and focal segmental glomerulosclerosis. Downregulation of CCN1 was significantly greater in diseased kidneys with severe mesangial expansion. CCN1 protein was also localized in the thick ascending limb of Henle's loop, distal and proximal tubules, and collecting ducts, which was not altered in diseased kidneys. In vitro, recombinant CCN1 protein enhanced endothelial cell adhesion, whereas it prominently inhibited mesangial cell adhesion. CCN1 also completely suppressed mesangial cell migration, suggesting its role as a mesangial-repellent factor. In cultured podocytes, CCN1 markedly induced the expression of cyclin-dependent kinase inhibitor p27Kip1 as well as synaptopodin in a dose-dependent manner and suppressed podocyte migration. These data indicate that CCN1 is expressed in podocytes, can act on glomerular cells to modulate glomerular remodeling, and is downregulated in diseased kidneys, suggesting that impairment of CCN1 expression in podocytes may contribute to the progression of glomerular disease with mesangial expansion.
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Truong, Luan D. y Steven S. Shen. "Immunohistochemical Diagnosis of Renal Neoplasms". Archives of Pathology & Laboratory Medicine 135, n.º 1 (1 de enero de 2011): 92–109. http://dx.doi.org/10.5858/2010-0478-rar.1.
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Abstract Context—Histologic diagnosis of renal neoplasm is usually straightforward by routine light microscopy. However, immunomarkers may be essential in several contexts, including differentiating renal from nonrenal neoplasms, subtyping of renal cell carcinoma (RCC), and diagnosing rare types of renal neoplasms or metastatic RCC in small biopsy specimens. Objective—To provide a comprehensive review of the diagnostic utility of immunomarkers for renal neoplasms. Design—This review is based on published literature and personal experience. Conclusions—The following markers may have diagnostic utility in various diagnostic contexts: cytokeratins, vimentin, α-methylacyl coenzyme A racemase, carbonic anhydrase IX, PAX2, PAX8, RCC marker, CD10, E-cadherin, kidney-specific cadherin, parvalbumin, claudin-7, claudin-8, S100A1, CD82, CD117, TFE3, thrombomodulin, uroplakin III, p63, and S100P. Cytokeratins are uniformly expressed by RCC, albeit in a somewhat limited amount in some subtypes, requiring broad-spectrum anti-CK antibodies, including both low– and high–molecular-weight cytokeratins. PAX2 and PAX8 are sensitive and relatively specific markers for renal neoplasm, regardless of subtype. CD10 and RCC marker are sensitive to renal cell neoplasms derived from proximal tubules, including clear cell and papillary RCCs. Kidney-specific cadherin, parvalbumin, claudin-7, and claudin-8 are sensitive markers for renal neoplasms from distal portions of the nephron, including chromophobe RCC and oncocytoma. CK7 and α-methylacyl coenzyme A racemase are sensitive markers for papillary RCC; TFE3 expression is essential in confirming the diagnosis of Xp11 translocation RCC. The potentially difficult differential diagnosis between chromophobe RCC and oncocytoma may be facilitated by S100A1 and CD82. Thrombomodulin, uroplakin III, p63, and S100P are useful markers for urothelial carcinoma. Together with high–molecular-weight cytokeratins, PAX2, and PAX8, they can help differentiate renal pelvic urothelial carcinoma from collecting duct RCC. A sensitive marker for sarcomatoid RCC is still not available. Immunomarkers are most often used for diagnosing metastatic RCC. Compared with primary RCC, expression of the above-mentioned markers is often less frequent and less diffuse in the metastatic setting. Recognizing the variable sensitivity and specificity of these markers, it is important to include at least CD10, RCC marker, PAX2, and PAX8 in the diagnostic panel.
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Schnabel, E., J. M. Anderson y M. G. Farquhar. "The tight junction protein ZO-1 is concentrated along slit diaphragms of the glomerular epithelium." Journal of Cell Biology 111, n.º 3 (1 de septiembre de 1990): 1255–63. http://dx.doi.org/10.1083/jcb.111.3.1255.
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The foot processes of glomerular epithelial cells of the mammalian kidney are firmly attached to one another by shallow intercellular junctions or slit diaphragms of unknown composition. We have investigated the molecular nature of these junctions using an antibody that recognizes ZO-1, a protein that is specific for the tight junction or zonula occludens. By immunoblotting the affinity purified anti-ZO-1 IgG recognizes a single 225-kD band in kidney cortex and in slit diaphragm-enriched fractions as in other tissues. When ZO-1 was localized by immunofluorescence in kidney tissue of adult rats, the protein was detected in epithelia of all segments of the nephron, but the glomerular epithelium was much more intensely stained than any other epithelium. Among tubule epithelia the signal for ZO-1 correlated with the known fibril content and physiologic tightness of the junctions, i.e., it was highest in distal and collecting tubules and lowest in the proximal tubule. By immunoelectron microscopy ZO-1 was found to be concentrated on the cytoplasmic surface of the tight junctional membrane. Within the glomerulus ZO-1 was localized predominantly in the epithelial foot processes where it was concentrated precisely at the points of insertion of the slit diaphragms into the lateral cell membrane. Its distribution appeared to be continuous along the continuous slit membrane junction. When ZO-1 was localized in differentiating glomeruli in the newborn rat kidney, it was present early in development when the apical junctional complexes between presumptive podocytes are composed of typical tight and adhering junctions. It remained associated with these junctions during the time they migrate down the lateral cell surface, disappear and are replaced by slit diaphragms. The distribution of ZO-1 and the close developmental relationship between the two junctions suggest that the slit diaphragm is a variant of the tight junction that shares with it at least one structural protein and the functional property of defining distinctive plasmalemmal domains. The glomerular epithelium is unique among renal epithelia in that ZO-1 is present, but the intercellular spaces are wide open and no fibrils are seen by freeze fracture. The presence of ZO-1 along slit membranes indicates that expression of ZO-1 alone does not lead to tight junction assembly.
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Lamontagne, Joseph O., Hui Zhang, Alia M. Zeid, Karin Strittmatter, Alicia D. Rocha, Trevor Williams, Sheryl Zhang y Alexander G. Marneros. "Transcription factors AP-2α and AP-2β regulate distinct segments of the distal nephron in the mammalian kidney". Nature Communications 13, n.º 1 (25 de abril de 2022). http://dx.doi.org/10.1038/s41467-022-29644-3.
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AbstractTranscription factors AP-2α and AP-2β have been suggested to regulate the differentiation of nephron precursor populations towards distal nephron segments. Here, we show that in the adult mammalian kidney AP-2α is found in medullary collecting ducts, whereas AP-2β is found in distal nephron segments except for medullary collecting ducts. Inactivation of AP-2α in nephron progenitor cells does not affect mammalian nephrogenesis, whereas its inactivation in collecting ducts leads to defects in medullary collecting ducts in the adult. Heterozygosity for AP-2β in nephron progenitor cells leads to progressive distal convoluted tubule abnormalities and β-catenin/mTOR hyperactivation that is associated with renal fibrosis and cysts. Complete loss of AP-2β in nephron progenitor cells caused an absence of distal convoluted tubules, renal cysts, and fibrosis with β-catenin/mTOR hyperactivation, and early postnatal death. Thus, AP-2α and AP-2β have non-redundant distinct spatiotemporal functions in separate segments of the distal nephron in the mammalian kidney.
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Matsui, Isao, Ayumi Matsumoto, Kazunori Inoue, Yusuke Katsuma, Seiichi Yasuda, Karin Shimada, Yusuke Sakaguchi et al. "Single cell RNA sequencing uncovers cellular developmental sequences and novel potential intercellular communications in embryonic kidney". Scientific Reports 11, n.º 1 (8 de enero de 2021). http://dx.doi.org/10.1038/s41598-020-80154-y.
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AbstractKidney development requires the coordinated growth and differentiation of multiple cells. Despite recent single cell profiles in nephrogenesis research, tools for data analysis are rapidly developing, and offer an opportunity to gain additional insight into kidney development. In this study, single-cell RNA sequencing data obtained from embryonic mouse kidney were re-analyzed. Manifold learning based on partition-based graph-abstraction coordinated cells, reflecting their expected lineage relationships. Consequently, the coordination in combination with ForceAtlas2 enabled the inference of parietal epithelial cells of Bowman’s capsule and the inference of cells involved in the developmental process from the S-shaped body to each nephron segment. RNA velocity suggested developmental sequences of proximal tubules and podocytes. In combination with a Markov chain algorithm, RNA velocity suggested the self-renewal processes of nephron progenitors. NicheNet analyses suggested that not only cells belonging to ureteric bud and stroma, but also endothelial cells, macrophages, and pericytes may contribute to the differentiation of cells from nephron progenitors. Organ culture of embryonic mouse kidney demonstrated that nerve growth factor, one of the nephrogenesis-related factors inferred by NicheNet, contributed to mitochondrial biogenesis in developing distal tubules. These approaches suggested previously unrecognized aspects of the underlying mechanisms for kidney development.
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Matsui, Isao, Ayumi Matsumoto, Kazunori Inoue, Yusuke Katsuma, Seiichi Yasuda, Karin Shimada, Yusuke Sakaguchi et al. "Single cell RNA sequencing uncovers cellular developmental sequences and novel potential intercellular communications in embryonic kidney". Scientific Reports 11, n.º 1 (8 de enero de 2021). http://dx.doi.org/10.1038/s41598-020-80154-y.
Texto completoResumen
AbstractKidney development requires the coordinated growth and differentiation of multiple cells. Despite recent single cell profiles in nephrogenesis research, tools for data analysis are rapidly developing, and offer an opportunity to gain additional insight into kidney development. In this study, single-cell RNA sequencing data obtained from embryonic mouse kidney were re-analyzed. Manifold learning based on partition-based graph-abstraction coordinated cells, reflecting their expected lineage relationships. Consequently, the coordination in combination with ForceAtlas2 enabled the inference of parietal epithelial cells of Bowman’s capsule and the inference of cells involved in the developmental process from the S-shaped body to each nephron segment. RNA velocity suggested developmental sequences of proximal tubules and podocytes. In combination with a Markov chain algorithm, RNA velocity suggested the self-renewal processes of nephron progenitors. NicheNet analyses suggested that not only cells belonging to ureteric bud and stroma, but also endothelial cells, macrophages, and pericytes may contribute to the differentiation of cells from nephron progenitors. Organ culture of embryonic mouse kidney demonstrated that nerve growth factor, one of the nephrogenesis-related factors inferred by NicheNet, contributed to mitochondrial biogenesis in developing distal tubules. These approaches suggested previously unrecognized aspects of the underlying mechanisms for kidney development.
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Miao, Zhen, Michael S. Balzer, Ziyuan Ma, Hongbo Liu, Junnan Wu, Rojesh Shrestha, Tamas Aranyi et al. "Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets". Nature Communications 12, n.º 1 (15 de abril de 2021). http://dx.doi.org/10.1038/s41467-021-22266-1.
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AbstractDetermining the epigenetic program that generates unique cell types in the kidney is critical for understanding cell-type heterogeneity during tissue homeostasis and injury response. Here, we profile open chromatin and gene expression in developing and adult mouse kidneys at single cell resolution. We show critical reliance of gene expression on distal regulatory elements (enhancers). We reveal key cell type-specific transcription factors and major gene-regulatory circuits for kidney cells. Dynamic chromatin and expression changes during nephron progenitor differentiation demonstrates that podocyte commitment occurs early and is associated with sustainedFoxl1expression. Renal tubule cells follow a more complex differentiation, whereHfn4ais associated with proximal andTfap2bwith distal fate. Mapping single nucleotide variants associated with human kidney disease implicates critical cell types, developmental stages, genes, and regulatory mechanisms. The single cell multi-omics atlas reveals key chromatin remodeling events and gene expression dynamics associated with kidney development.
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Wilson, Sean B., Sara E. Howden, Jessica M. Vanslambrouck, Aude Dorison, Jose Alquicira-Hernandez, Joseph E. Powell y Melissa H. Little. "DevKidCC allows for robust classification and direct comparisons of kidney organoid datasets". Genome Medicine 14, n.º 1 (22 de febrero de 2022). http://dx.doi.org/10.1186/s13073-022-01023-z.
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Abstract Background While single-cell transcriptional profiling has greatly increased our capacity to interrogate biology, accurate cell classification within and between datasets is a key challenge. This is particularly so in pluripotent stem cell-derived organoids which represent a model of a developmental system. Here, clustering algorithms and selected marker genes can fail to accurately classify cellular identity while variation in analyses makes it difficult to meaningfully compare datasets. Kidney organoids provide a valuable resource to understand kidney development and disease. However, direct comparison of relative cellular composition between protocols has proved challenging. Hence, an unbiased approach for classifying cell identity is required. Methods The R package, scPred, was trained on multiple single cell RNA-seq datasets of human fetal kidney. A hierarchical model classified cellular subtypes into nephron, stroma and ureteric epithelial elements. This model, provided in the R package DevKidCC (github.com/KidneyRegeneration/DevKidCC), was then used to predict relative cell identity within published kidney organoid datasets generated using distinct cell lines and differentiation protocols, interrogating the impact of such variations. The package contains custom functions for the display of differential gene expression within cellular subtypes. Results DevKidCC was used to directly compare between distinct kidney organoid protocols, identifying differences in relative proportions of cell types at all hierarchical levels of the model and highlighting variations in stromal and unassigned cell types, nephron progenitor prevalence and relative maturation of individual epithelial segments. Of note, DevKidCC was able to distinguish distal nephron from ureteric epithelium, cell types with overlapping profiles that have previously confounded analyses. When applied to a variation in protocol via the addition of retinoic acid, DevKidCC identified a consequential depletion of nephron progenitors. Conclusions The application of DevKidCC to kidney organoids reproducibly classifies component cellular identity within distinct single-cell datasets. The application of the tool is summarised in an interactive Shiny application, as are examples of the utility of in-built functions for data presentation. This tool will enable the consistent and rapid comparison of kidney organoid protocols, driving improvements in patterning to kidney endpoints and validating new approaches.
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Minuth, Will W. "The interstitium at the developing nephron in the fetal kidney during advanced pregnancy — a microanatomical inventory". Molecular and Cellular Pediatrics 9, n.º 1 (26 de agosto de 2022). http://dx.doi.org/10.1186/s40348-022-00149-9.
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Abstract Background A series of noxae can evoke the termination of nephron formation in preterm and low birth weight babies. This results in oligonephropathy with severe consequences for health in the later life. Although the clinical parameters have been extensively investigated, little is known about the initial damage. Previous pathological findings indicate the reduction in width of the nephrogenic zone and the lack of S-shaped bodies. Current morphological investigations suggest that due to the mutual patterning beside the forming nephron, also its structural neighbors, particularly the interjacent interstitium, must be affected. However, beside the findings on integrative and mastering functions, systematic microanatomical data explaining the configuration of the interstitium at the developing nephron in the fetal kidney during advanced pregnancy is not available. Therefore, this work explains the typical features. Results The generated data depicts that the progenitor cells, nephrogenic niche, pretubular aggregate, and mesenchymal-to-epithelial transition are restricted to the subcapsular interstitium. During the proceeding development, only the distal pole of the renal vesicles and comma- and S-shaped bodies stays in further contact with it. The respective proximal pole is positioned opposite the peritubular interstitium at the connecting tubule of an underlying but previously formed nephron. The related medial aspect faces the narrow peritubular interstitium of a collecting duct (CD) ampulla first only at its tip, then at its head, conus, and neck, and finally at the differentiating CD tubule. The lateral aspect starts at the subcapsular interstitium, but then it is positioned along the wide perivascular interstitium of the neighboring ascending perforating radiate artery. When the nephron matures, the interstitial configuration changes again. Conclusions The present investigation illustrates that the interstitium at the forming nephron in the fetal kidney consists of existing, transient, stage-specific, and differently far matured compartments. According to the developmental needs, it changes its shape by formation, degradation, fusion, and rebuilding.