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1
Huang, Kun, Sudha Garimella, Alyssa Clay-Gilmour, Lucia Vojtech, Bridget Armstrong, Madison Bessonny, and Alexis Stamatikos. "Comparison of Human Urinary Exosomes Isolated via Ultracentrifugation Alone versus Ultracentrifugation Followed by SEC Column-Purification." Journal of Personalized Medicine 12, no. 3 (February 24, 2022): 340. http://dx.doi.org/10.3390/jpm12030340.
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Chronic kidney disease is a progressive, incurable condition that involves a gradual loss of kidney function. While there are no non-invasive biomarkers available to determine whether individuals are susceptible to developing chronic kidney disease, small RNAs within urinary exosomes have recently emerged as a potential candidate to use for assessing renal function. Ultracentrifugation is the gold standard for urinary exosome isolation. However, extravesicular small RNA contamination can occur when isolating exosomes from biological fluids using ultracentrifugation, which may lead to misidentifying the presence of certain small RNA species in human urinary exosomes. Therefore, we characterized human urinary exosomal preparations isolated by ultracentrifugation alone, or via ultracentrifugation followed by size exclusion chromatography (SEC) column-purification. Using nanoparticle tracking analysis, we identified SEC fractions containing robust amounts of exosome-sized particles, that we further characterized using immunoblotting. When compared to exosomal preparations isolated by ultracentrifugation only, SEC fractionated exosomal preparations showed higher levels of the exosome-positive marker CD81. Moreover, while the exosome-negative marker calnexin was undetectable in SEC fractionated exosomal preparations, we did observe calnexin detection in the exosomal preparations isolated by ultracentrifugation alone, which implies contamination in these preparations. Lastly, we imaged SEC fractionated exosomal preparations using transmission electron microscopy to confirm these preparations contained human urinary exosomes. Our results indicate that combining ultracentrifugation and SEC column-purification exosome isolation strategies is a powerful approach for collecting contaminant-free human urinary exosomes and should be considered when exosomes devoid of contamination are needed for downstream applications.
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Abdeen, Ahmed, Hiroko Sonoda, Ragab El-Shawarby, Saki Takahashi, and Masahiro Ikeda. "Urinary excretion pattern of exosomal aquaporin-2 in rats that received gentamicin." American Journal of Physiology-Renal Physiology 307, no. 11 (December 1, 2014): F1227—F1237. http://dx.doi.org/10.1152/ajprenal.00140.2014.
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Urinary exosomes are nano-sized vesicles secreted into urine from all types of renal epithelial cells and are known to contain possible biomarker proteins for renal diseases. Gentamicin has been reported to decrease the level of renal aquaporin (AQP)2, which is known to be mainly expressed in renal collecting ducts and excreted into the urine via exosomes. In the present study, we investigated whether urinary exosomal AQP2 could serve as a potential biomarker for gentamicin-induced nephrotoxicity, especially collecting duct cell dysfunction. Gentamicin was given to rats intraperitoneally once every day starting on day 0. Gentamicin significantly increased the plasma creatinine concentration from day 5 and beyond. Also, gentamicin induced polyuria and a defective urine concentration mechanism on day 7, suggesting gentamicin-induced collecting duct cell dysfunction. Immunoblot analysis showed that gentamicin significantly increased urinary exosomal AQP2 excretion on day 1 but decreased it on day 7 compared with the control group. Similarly, increased excretion of exosomal tumor susceptibility gene 101 protein, frequently used as an exosome marker protein, was observed on day 1. However, gentamicin did not significantly affect the urinary excretion of exosomal tumor susceptibility gene 101 on day 7. Gentamicin slightly decreased renal AQP2 expression on day 2 and markedly decreased it on day 8. These data strongly suggest that the use of urinary exosomal AQP2 as a biomarker may allow detection of gentamicin-induced collecting duct cell dysfunction. Furthermore, urinary exosomal AQP2 might also be useful for the early detection of gentamicin-induced renal injury in addition to collecting duct injury.
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Cheruvanky, Anita, Hua Zhou, Trairak Pisitkun, Jeffrey B. Kopp, Mark A. Knepper, Peter S. T. Yuen, and Robert A. Star. "Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator." American Journal of Physiology-Renal Physiology 292, no. 5 (May 2007): F1657—F1661. http://dx.doi.org/10.1152/ajprenal.00434.2006.
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Urinary exosomes are excreted from all nephron segments and may serve as biomarkers for classifying renal diseases. Isolation of urinary exosomes by the established ultracentrifugation method has some limitations for use in a clinical laboratory. We sought a rapid and simple way to obtain urinary exosomes. We used a commercially available nanomembrane concentrator to enrich exosomes from urine by centrifugation at 3,000 g for 10–30 min. Urinary exosomal markers tumor susceptibility gene 101, aquaporin-2, neuron-specific enolase, annexin V, angiotensin-converting enzyme, and podocalyxin (PODXL) were recovered from the nanomembrane concentrator and detected by Western blotting, and typical features of urinary vesicles were found by electron microscopy. Exosomal markers were detected in as little as 0.5 ml of urine. By the nanomembrane method, exosomal proteins could be recovered from urine samples frozen at −80°C or refrigerated overnight at 4°C then stored at −80°C. By enriching exosomes we could detect PODXL, a podocyte marker, which decreased by 71% in five male patients with focal segmental glomerulosclerosis and abundant proteinuria. We conclude that 1) use of a nanomembrane concentrator simplifies and accelerates the enrichment of urinary exosomes; and 2) the nanomembrane concentrator can concentrate exosomal proteins from clinical urine samples. This enhanced method may accelerate the translation of urinary exosomal biomarkers from bench to bedside for the diagnosis, classification, and prognostication of renal diseases.
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Huang, Zhibin, Yong Zhang, Jianhua Zhou, and Yu Zhang. "Urinary Exosomal miR-193a Can Be a Potential Biomarker for the Diagnosis of Primary Focal Segmental Glomerulosclerosis in Children." BioMed Research International 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/7298160.
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Background. Glomerular upregulation of miR-193a has been detected in primary focal segmental glomerulosclerosis (FSGS) but not in other glomerular diseases. We aimed to isolate exosomes from urine of children with primary FSGS and to assess the diagnostic potential of urinary exosomal miR-193a for primary FSGS. Methods. The first morning urine samples were collected from children with primary FSGS (n=8) and minimal change disease (MCD, n=5). Isolated urinary exosomes were confirmed by electron microscopy and Western blotting. Urinary exosomal microRNA was extracted, and the expression levels of exosomal miR-193a were quantified by real-time PCR. The diagnosis value of urinary exosomal miR-193a levels for primary FSGS was evaluated by ROC analysis. Results. The isolated vesicles were qualitatively compatible with exosomes. The levels of urinary exosomal miR-193a were significantly higher in children with primary FSGS than those in children with MCD. Moreover, the area under the ROC for the diagnosis of primary FSGS using urinary exosomal miR-193a was 0.85. Conclusions. A significant increase in the levels of urinary exosomal miR-193a in primary FSGS patients compared to those in MCD ones was observed. This study suggests that urinary exosomal miR-193a may be a new noninvasive biomarker for the diagnosis of primary FSGS.
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Garcia-Vives, Eloi, Cristina Solé, Teresa Moliné, Marta Vidal, Irene Agraz, Josep Ordi-Ros, and Josefina Cortés-Hernández. "The Urinary Exosomal miRNA Expression Profile is Predictive of Clinical Response in Lupus Nephritis." International Journal of Molecular Sciences 21, no. 4 (February 18, 2020): 1372. http://dx.doi.org/10.3390/ijms21041372.
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Data on exosomal-derived urinary miRNAs have identified several miRNAs associated with disease activity and fibrosis formation, but studies on prognosis are lacking. We conducted a qPCR array screening on urinary exosomes from 14 patients with biopsy-proven proliferative lupus glomerulonephritis with a renal outcome of clinical response (n = 7) and non-response (n = 7) following therapy. Validation studies were performed by qRT-PCR in a new lupus nephritis (LN) cohort (responders = 22 and non-responders = 21). Responder patients expressed significantly increased levels of miR-31, miR-107, and miR-135b-5p in urine and renal tissue compared to non-responders. MiR-135b exhibited the best predictive value to discriminate responder patients (area under the curve = 0.783). In vitro studies showed exosome-derived miR-31, miR-107, and miR-135b-5p expression to be mainly produced by tubular renal cells stimulated with inflammatory cytokines (e.g IL1, TNFα, IFNα and IL6). Uptake of urinary exosomes from responders by mesangial cells was superior compared to that from non-responders (90% vs. 50%, p < 0.0001). HIF1A was identified as a potential common target, and low protein levels were found in non-responder renal biopsies. HIF1A inhibition reduced mesangial proliferation and IL-8, CCL2, CCL3, and CXCL1 mesangial cell production and IL-6/VCAM-1 in endothelial cells. Urinary exosomal miR-135b-5p, miR-107, and miR-31 are promising novel markers for clinical outcomes, regulating LN renal recovery by HIF1A inhibition.
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Yu, Yanting, Zhiyun Ren, Anni Xie, Yutao Jia, Ying Xue, Ping Wang, Daxi Ji, and Xiaoyan Wang. "Assessment of Urinary Exosomal NHE3 as a Biomarker of Acute Kidney Injury." Diagnostics 12, no. 11 (October 30, 2022): 2634. http://dx.doi.org/10.3390/diagnostics12112634.
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The diagnosis of acute kidney injury (AKI) traditionally depends on the serum creatinine (Scr) and urine output, which lack sufficient sensitivity and specificity. Using urinary exosomes as a biomarker has unique advantages. To assess whether urinary exosomal Na+/H+ exchanger isoform 3 (NHE3) protein could serve as a biomarker of AKI, we constructed four AKI rat models: cisplatin (7.5 mg/kg) injected intraperitoneally (IP), furosemide (20 mg/kg, IP) with a low-NaCl (0.03%) diet, a low-NaCl (0.03%) diet with candesartan (1 mg/kg, IP) and bilateral ischemia and reperfusion (I/R) injury for 40 min. Additionally, we assessed six sepsis-associated AKI patients and six healthy volunteers. Urinary exosomes were extracted by ultracentrifugation, and the NHE3 protein abundance was tested by immunoblotting for all the AKI rats and human subjects. The isolated cup-shaped particles with an average diameter of 70 nm and enrichment in CD63 were identified as exosomes. NHE3 abundance was six times higher in exosomes than in the whole urine. In cisplatin-induced AKI rats, urinary exosomal NHE3 was increased on day 2, one day earlier than the increases in Scr and blood urea nitrogen (BUN). In additional rats, urinary exosomal NHE3 decreased along with the decline in Scr after EPO pretreatment. In volume-depletion AKI induced by furosemide injection with a low-NaCl diet, the urinary exosomal NHE3 expression was higher than that in the control. Under a low-NaCl diet with candesartan-related AKI, the urinary exosomal NHE3 was elevated on day 5, earlier than Scr. In I/R-injury AKI, the urinary exosomal NHE3 was also raised compared with that in the control. In humans, the urinary exosomal NHE3 level was also elevated in sepsis-associated AKI patients in comparison with that in the healthy volunteers. The urinary exosomal NHE3 was increased in multiple AKI; it may be used as a diagnostic biomarker of AKI.
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Cao, Yuhan, Yuanhui Shi, Yuwei Wang, Yanlang Yang, Wenjun Guo, Cuifeng Zhang, Wenjun Pei, and Cong Fu. "Exosomal hsa_circ_0008925 from Urine Is Related to Chronic Renal Fibrosis." Disease Markers 2022 (February 18, 2022): 1–10. http://dx.doi.org/10.1155/2022/1899282.
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At present, there is no noninvasive biomarker of renal fibrosis. The potential diagnostic value of urinary exosome-derived circRNAs from glomerular disease patients for renal fibrosis is still uncertain. Here, we first detected the expression of hsa_circ_0008925 in TGF-β1-cultured HK-2 cell-derived exosomes. Secondly, we collected urine samples from 95 biopsy-proven glomerular disease patients and 34 healthy controls. The expression of hsa_circ_0008925 was analyzed, and the correlation with renal function and pathological changes was calculated. The receiver operating characteristic (ROC) curve for the diagnosis of renal fibrosis was performed. The results showed that in exosomes derived from TGF-β1-cultured HK-2 cells, the expression of hsa_circ_0008925 was increased compared with normal cultured. Further, the expression level of hsa_circ_0008925 was increased in urinary exosomes from renal fibrosis patients and correlated with serum creatinine, blood urea nitrogen (BUN), estimated glomerular filtration rate, and cystatin C. The level of hsa_circ_0008925 was furthermore correlated with the score of tubulointerstitial fibrosis (TIF) and the score of glomerular sclerosis. The ROC curve showed that hsa_circ_0008925 can diagnose renal fibrosis at a cut-off value of 0.093 with a sensitivity of 52.2% and specificity of 96.4%. In summary, we indicated that urinary exosomal hsa_circ_0008925 could be acted as a noninvasive biomarker for renal fibrosis in glomerular diseases patients.
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Chen, Chen, Anquan Shang, Zujun Sun, Yuting Gao, Jingjuan Huang, Yili Ping, Wenjing Chang, et al. "Urinary Exosomal Long Noncoding RNA TERC as a Noninvasive Diagnostic and Prognostic Biomarker for Bladder Urothelial Carcinoma." Journal of Immunology Research 2022 (January 25, 2022): 1–9. http://dx.doi.org/10.1155/2022/9038808.
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Purpose. Bladder cancer is one of the most common urological malignancies worldwide, and approximately 90% of bladder cancer cases are histologically typed as bladder urothelial carcinoma (BLCA). Exosomes are 30 to 200 nm extracellular vesicles that transport microRNAs, long noncoding RNAs (lncRNAs), mRNAs, circular RNAs, and proteins across tissues and through circulation. Urinary exosomes may contain genetic information from tumor cells. Herein, we explored the clinical significance of urinary exosomal lncRNA telomerase RNA component (TERC) levels to provide an urgently needed diagnostic and prognostic biomarker for BLCA. Materials and Methods. In this study, we used RNA-sequencing of samples from four BLCA patients and three healthy controls to identify that TERC was differentially expressed in urinary exosomes. We then used quantitative PCR in different types of clinical samples to validate the biomarker and analyzed results using receiver operating characteristic curves. Results. We found that TERC was significantly upregulated in urinary exosomes from BLCA patients compared with those from healthy controls ( P < 0.0001 ). Urinary exosomal TERC showed higher sensitivity (78.65%) and accuracy (77.78%) than existing indicators including nuclear matrix protein-22 and urine cytometry. Using the cut-off value 4.302, the area under the curve for urinary exosomal TERC was 0.836 (95% confidence interval: 0.768–0.891, P < 0.0001 ). Furthermore, this noninvasive assay could distinguish low-grade and high-grade tumors ( P = 0.0153 ). Conclusions. TERC is enriched in urinary exosomes from BLCA patients. Urinary exosomal TERC could become a diagnostic and prognostic biomarker for BLCA that allows clinicians to realize noninvasive detection of BLCA.
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Li, Guorong, Nora Mallouk, Pascale Flandrin, Arnauld Garcin, Claude Lambert, Sid Ali Berremila, Hocine Habchi, and Nicolas Mottet. "Presence of Urinary Exosomes for Liquid Biopsy of Clear Cell Renal Cell Carcinoma: Protocol for a Pilot Feasibility Study." JMIR Research Protocols 10, no. 7 (July 20, 2021): e24423. http://dx.doi.org/10.2196/24423.
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Background Approximately 70%-80% of kidney cancers are clear cell renal cell carcinomas (CCRCCs). Patient management is based on imaging (abdominal ultrasound and computerized tomography), surgical excision of the tumor, and pathological analysis. A tissue biopsy is therefore necessary to confirm the diagnosis and avoid unnecessary nephrectomy. For metastatic cancers, a tissue biopsy is essential for establishing the targeted therapy. This biopsy of tumor material is invasive and painful. Other techniques such as liquid biopsy would help reduce the need for tissue biopsy. The development of a simple biological test for diagnosis is essential. CA9 is a powerful marker for the diagnosis of CCRCC. Exosomes have become a major source of liquid biopsy because they carry tumor proteins, RNA, and lipids. Urine is the most convenient biological liquid for exosome sampling. Objective The aim of this study (PEP-C study) is mainly to determine whether it is possible to detect urinary exosomal CA9 for the molecular diagnosis of CCRCC. Methods This study will include 60 patients with CCRCC and 40 noncancer patients. Exosomes will be isolated from urine samples and exosomal CA9 will be detected by transmission electron microscopy, flow cytometry, and reverse transcription-quantitative polymerase chain reaction. Results This study is currently underway with funding support from the CHU Saint-Etienne of France. Conclusions We expect to demonstrate that urinary tumor exosomes could be a novel liquid biopsy to diagnose CCRCC and to guide clinicians in treatment decision-making. Trial Registration ClinicalTrials.gov NCT04053855; https://clinicaltrials.gov/ct2/show/NCT04053855 International Registered Report Identifier (IRRID) DERR1-10.2196/24423
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Riffo-Campos, Angela L., Javier Perez-Hernandez, Olga Martinez-Arroyo, Ana Ortega, Ana Flores-Chova, Josep Redon, and Raquel Cortes. "Biofluid Specificity of Long Non-Coding RNA Profile in Hypertension: Relevance of Exosomal Fraction." International Journal of Molecular Sciences 23, no. 9 (May 6, 2022): 5199. http://dx.doi.org/10.3390/ijms23095199.
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Non-coding RNA (ncRNA)-mediated targeting of various genes regulates the molecular mechanisms of the pathogenesis of hypertension (HTN). However, very few circulating long ncRNAs (lncRNAs) have been reported to be altered in essential HTN. The aim of our study was to identify a lncRNA profile in plasma and plasma exosomes associated with urinary albumin excretion in HTN by next-generation sequencing and to assess biological functions enriched in response to albuminuria using GO and KEGG analysis. Plasma exosomes showed higher diversity and fold change of lncRNAs than plasma, and low transcript overlapping was found between the two biofluids. Enrichment analysis identified different biological pathways regulated in plasma or exosome fraction, which were implicated in fatty acid metabolism, extracellular matrix, and mechanisms of sorting ncRNAs into exosomes, while plasma pathways were implicated in genome reorganization, interference with RNA polymerase, and as scaffolds for assembling transcriptional regulators. Our study found a biofluid specific lncRNA profile associated with albuminuria, with higher diversity in exosomal fraction, which identifies several potential targets that may be utilized to study mechanisms of albuminuria and cardiovascular damage.
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El Fekih, Rania, James Hurley, Vasisht Tadigotla, Areej Alghamdi, Anand Srivastava, Christine Coticchia, John Choi, et al. "Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection." Journal of the American Society of Nephrology 32, no. 4 (March 3, 2021): 994–1004. http://dx.doi.org/10.1681/asn.2020060850.
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BackgroundDeveloping a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells’ proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection.MethodsUsing 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets.ResultsAn exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature’s negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell–mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature’s negative predictive value was 90.6% and its positive predictive value was 77.8%.ConclusionsOur findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.
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Roberts, Douglas, Emily Mitsock, Olubode Ogunlusi, Seth Yu, and Johan Skog. "Biomarker screening for the early detection of prostate cancer using an exosomal-enrichment RNA liquid biopsy test." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15553-e15553. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15553.
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e15553 Background: Prostate cancer is one of the most common cancers in men, with approximately 10% of all new cancer cases and ~5% of all cancer deaths in 2019. The standard test for prostate cancer is the Prostate Serum Antigen (PSA) test. The PSA test suffers from low specificity (20-40%) in patients including ‘grey zone’ levels (4-10 ng/mL); moreover, the PSA test fails to identify patients with high-risk cancers. Previously we developed ExoDx Prostate Intelliscore (EPI), a urine-based exosome prostate cancer test optimized to rule out the need for a biopsy (risk stratification for high-grade prostate cancer). This study utilized a next generation exosome-based test that specifically enriches a subtype of prostate cancer exosomes from urine. Early detection of prostate cancer via a non-invasive method is desirable and the identification of patients with high-risk cancer is critical. Here we describe the development of a prostate-specific urinary exosome test for the identification of patients with prostate cancer. Methods: We have developed a prostate-specific enrichment method to isolate exosomes of prostate origin from urine samples. Using an affinity-based method against surface marker proteins found on prostate cells, we were able to selectively enrich for exosomes shed by the prostate gland with demonstrated specificity. Subsequent analysis of exosomal nucleic acids enables a promising panel of gene expression biomarkers capable of distinguishing patients with prostate cancer from healthy individuals. Results: RNA from prostate cancer enriched exosomes was compared to total exosomes from urine. Enrichment of prostate cancer specific exosomes significantly enhanced the RNA signature compared to total urine exosomes. Conclusions: Prostate cancer tests have recently been developed for RNA signatures in urine. Exosomes provide a source of nucleic acids as they are actively shed continuously from living cells as part of their normal life cycle. The urine exosomes can be used for total RNA transcriptome analysis and are therefore a very rich source of biomarkers for prostate cancer that can be tailored to different clinical indications. An affinity-based enrichment for tissue-specific exosomes allow for better resolution of the gene expression profile from the tissue of interest and reduces the RNA targets from non-relevant processes of the bladder and kidneys. The gene signature identified in this ongoing study could potentially provide a non-invasive molecular means for the early diagnosis of prostate cancer.
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Ledet, Elisa M., Patrick J. Miller, Ratish Gambhira, Aryeneesh Dotiwala, and A. Oliver Sartor. "Characterization of plasma-derived and urinary exosomal microRNA from metastatic CRPC patients." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 248. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.248.
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248 Background: Exosomes are nano-sized (50-100nm) vesicles derived from normal and tumor cells that function in cell-cell communication. These vesicles and their nucleic acid cargo may potentially serve as biomarkers for assessment of risk stratification and therapeutic response. The goal of this study was to characterize exosome derived microRNA (miRNA) isolated from plasma (pExos) and urine (uExos) of metastatic CRPC patients. Methods: Plasma samples were obtained from 18 mCRPC patients and 1 normal control. Following exosome isolation, RNA extraction and library prep, paired-end sequencing was performed using Illumina Hi-Seq 2000. A bioinformatics pipeline was used for data processing including alignment, duplicate removal, normalization, and variant calling. Visualization and differential analyses were performed with SNP & Variation Suite v8.x. RNA derived from uExos was amplified using whole transcriptome amplification and interrogated with Prostate Cancer (PCa) miScript miRNA PCR Array. Results: Exosomes from both plasma and urine had similar amounts of miRNA/total RNA with average 34% miRNA (range 19%-51%). pExos had larger RNA fragments (range 10-333 nt) while uExos were more highly fragmented (range 10-60 nt). The amount of miRNA and fragmentation pattern was highly variable amongst patients. In pExos, RNA from PDPK1, USP9X, MAGI2, HMGA2 and PTGFR were present and previously shown in PCa. Also in pExos, miR941-2, miR4454, miR1302-2, miR143HG and miR22HG were annotated in prostate cancer patients; these miRNA have previously been identified in cancer. In uExos miR-16-5p and miR-375 were present and are shown to be differentially regulated in prostate cancer. Expression analyses will be presented. PCR validation is ongoing. Conclusions: The identification of cancer associated miRNA in pExos and uExos may potentially serve as biomarkers in mCRPC patients. The abundance and stability of miRNA contained in exosomes may provide insight into tumor evolution and disease progression. Additional studies evaluating the clinical relevance and prognostic value of exosomal miRNA are warranted.
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Higashijima, Yoshiki, Hiroko Sonoda, Saki Takahashi, Hiroaki Kondo, Kanako Shigemura, and Masahiro Ikeda. "Excretion of urinary exosomal AQP2 in rats is regulated by vasopressin and urinary pH." American Journal of Physiology-Renal Physiology 305, no. 10 (November 15, 2013): F1412—F1421. http://dx.doi.org/10.1152/ajprenal.00249.2013.
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Urinary exosomes are small vesicles secreted into urine from all renal epithelial cell types and known to contain proteins that are involved in renal secretion and reabsorption. Among these proteins, urinary exosomal aquaporin-2 (AQP2) has been suggested to be useful for diagnosis of renal disease. However, the mechanisms underlying the excretion of urinary exosomal AQP2 are largely unknown. In this study, we examined the mechanisms of urinary exosomal AQP2 excretion in vivo, using diuretics including furosemide (FS), an inhibitor of the sodium-potassium-chloride symporter; acetazolamide (ACTZ), an inhibitor of carbonic anhydrase; OPC-31260 (OPC), a vasopressin type 2 receptor antagonist; and NaHCO3, a urinary alkalizing agent. Samples of urine from rats were collected for 2 h just after treatment with each diuretic, and urinary exosomes were isolated by ultracentrifugation. Urinary exosomal AQP2 excretion was dramatically increased by treatment with FS accompanied by urine acidification or with ACTZ accompanied by urine alkalization. Immunohistochemistry showed that apical localization of AQP2 was clearly evident and the plasma vasopressin level was increased after each treatment. Although treatment with OPC alone had no significant effect, coadministration of OPC completely inhibited the FS-induced and partially reduced the ACTZ-induced responses, respectively. Treatment with NaHCO3 increased the excretion of urinary exosomal AQP2 accompanied by urine alkalization. This increased response was partially inhibited by coadministration of OPC. These data suggest that an increased plasma level of vasopressin promoted the excretion of urinary exosomal AQP2 and that urine alkalinization also increased it independently of vasopressin.
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Xiang, Xiaochao, Fulin Guan, Fenglong Jiao, Hang Li, Wanjun Zhang, Yangjun Zhang, and Weijie Qin. "A new urinary exosome enrichment method by a combination of ultrafiltration and TiO2 nanoparticles." Analytical Methods 13, no. 13 (2021): 1591–600. http://dx.doi.org/10.1039/d1ay00102g.
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The workflow of separation and enrichment of exosomes by ultrafiltration–TiO2. We proposed a new strategy for facile exosome isolation from human urine by utilizing the ultrafiltration technique and TiO2, which can significantly reduce urine volumes, increase exposure of the material to exosomes in urine and obtain high purity exosomes.
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Sonoda, Hiroko, Naoko Yokota-Ikeda, Sayaka Oshikawa, Yosuke Kanno, Kazuya Yoshinaga, Kazuyuki Uchida, Yuuji Ueda, et al. "Decreased abundance of urinary exosomal aquaporin-1 in renal ischemia-reperfusion injury." American Journal of Physiology-Renal Physiology 297, no. 4 (October 2009): F1006—F1016. http://dx.doi.org/10.1152/ajprenal.00200.2009.
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Urinary exosomes, secreted into urine from renal epithelial cells, are known to contain many types of renal functional membrane proteins. Here, we studied whether renal ischemia-reperfusion (I/R) affects urinary exosomal aquaporin-1 (AQP1) excretion in rats subjected to renal I/R and patients who underwent renal transplantation. Immunoblotting studies demonstrated reduction of the urinary exosomal AQP1 level even at 6 h after renal I/R, and the level continued to be low over 96 h after I/R. Renal AQP1 mRNA and protein analyses revealed that the decreased excretion of urinary exosomal AQP1 is associated with renal AQP1 protein retention in the early phase and with a decreased expression level of renal AQP1 in the later phase of renal I/R injury. Decreased abundance of urinary exosomal AQP1 in a recipient patient was also observed at 48 h after renal allograft transplantation. No significant decrease in urinary exosomal AQP1 was observed in a rat model of nephropathy or in patients with proteinuria. Our studies suggest that the renal AQP1 expression level is possibly controlled by its urinary exosomal excretion and indicate that urinary exosomal AQP1 is a novel urinary biomarker for renal I/R injury.
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Zhang, Jinshi, Yifan Zhu, Ruyi Cai, Juan Jin, and Qiang He. "Differential Expression of Urinary Exosomal Small RNAs in Idiopathic Membranous Nephropathy." BioMed Research International 2020 (December 29, 2020): 1–12. http://dx.doi.org/10.1155/2020/3170927.
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Background. Idiopathic membranous nephropathy (IMN) is a major cause of adult nephrotic syndromes, and reliable noninvasive biomarkers for diagnosis and monitoring are urgently needed. In this study, we performed small RNA (sRNA) sequencing to explore sRNA profiles of urinary exosomes derived from IMN patients and healthy controls (CON) to provide clues for identifying novel noninvasive sRNA biomarkers for IMN. Methods. Urine samples were collected from five healthy controls and six patients with IMN. High-throughput sequencing was used to screen sRNA expression profiles of urinary exosomes from patients with IMN in two independent cohorts. Results. Urinary exosomes were successfully isolated and used to obtain exosomal sRNAs. We screened 131 differentially expressed miRNAs, including 28 specifically expressed miRNAs, then explored the top 10 specifically expressed miRNAs in all IMN individuals. The specifically expressed miRNAs and differentially expressed miRNAs provide potential biomarkers for IMN. Additionally, we discovered numerous sRNAs derived from genomic repetitive sequences, which could represent an exciting new area of research. Conclusion. Herein, we revealed significant differences in expression profiles of urinary exosomal miRNAs and repetitive region-derived sRNAs between patients with IMN and healthy controls. The findings could facilitate the development of potential molecular targets for membranous nephropathy.
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Shirley, James Forrest, Joshua Drourr, W. Taylor Edwards, Kubra Tuna, Lisa K. Ryan, Abdel Alli, Ying Tang, and Sarah C. Glover. "Mast Cells in Patients with Hereditary α-Tryptasemia Promote HLA-DR Expression and a Th2-Polarizing Microenvironment in the Gastrointestinal Tract." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 192.13. http://dx.doi.org/10.4049/jimmunol.202.supp.192.13.
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Abstract Hereditary α-tryptasemia (HαT) is a recently identified, genetic disorder characterized by multisystem comorbidities resulting from increased monoallelic α-tryptase copy number (CN) at TPSAB1 (α-TPSAB1). Affected individuals frequently exhibit heterogeneous multisystem symptoms and comorbidities which negatively impact daily functioning and quality of life. In the cohorts examined thus far, functional dyspepsia and irritable bowel syndrome, were most frequently reported. However, the mechanism by which increased α-TPSAB1 CN produces GI disease is unknown. Tryptase is almost exclusively produced by mast cells (MC). In the gut, MC play important roles in immune responses, leukocyte recruitment, neuroimmune inflammation, and tissue repair. MC can also promote T-cell activation and polarization via cytokine secretion, co-stimulatory marker expression and MHC II antigen presentation. MCs also release exosomes, nanosized vesicles secreted by most cell types present in biological fluids such as blood, cerebrospinal fluid, and urine, which have a reported influence on T cell differentiation. In early experiments, we found increased numbers of GI MCs, activated T cells, and urinary exosomes in HαT patients compared to healthy donors. Thus, we evaluated MC surface antigen expression, exosome proteomics, and cytokine expression of exosome-treated T cells. We found increased HLA-DR and FcɛR1α expression in HαT-patient GI MCs, increased Th2 associated signaling proteins in HαT urinary exosomes, and elevated Th2 cytokine expression in HαT-exosome treated T cells. These results suggest that HαT GI morbidity involves aggravated MC hyperplasia and antigen presentation which promotes T cell activation and Th2 polarization.
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Kim, Mi Joung, Seong Jun Lim, Youngmin Ko, Hye Eun Kwon, Joo Hee Jung, Hyunwook Kwon, Heounjeong Go, et al. "Urinary Exosomal Cystatin C and Lipopolysaccharide Binding Protein as Biomarkers for Antibody−Mediated Rejection after Kidney Transplantation." Biomedicines 10, no. 10 (September 21, 2022): 2346. http://dx.doi.org/10.3390/biomedicines10102346.
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We aimed to discover and validate urinary exosomal proteins as biomarkers for antibody−mediated rejection (ABMR) after kidney transplantation. Urine and for-cause biopsy samples from kidney transplant recipients were collected and categorized into the discovery cohort (n = 36) and a validation cohort (n = 65). Exosomes were isolated by stepwise ultra-centrifugation for proteomic analysis to discover biomarker candidates for ABMR (n = 12). Of 1820 exosomal proteins in the discovery cohort, four proteins were specifically associated with ABMR: cystatin C (CST3), serum paraoxonase/arylesterase 1, retinol-binding protein 4, and lipopolysaccharide−binding protein (LBP). In the validation cohort, the level of urinary exosomal LBP was significantly higher in the ABMR group (n = 25) compared with the T-cell-mediated rejection (TCMR) group and the no major abnormality (NOMOA) group. Urinary exosomal CST3 level was significantly higher in the ABMR group compared with the control and NOMOA groups. Immunohistochemical staining showed that LBP and CST3 in the glomerulus were more abundant in the ABMR group compared with other groups. The combined prediction probability of urinary exosomal LBP and CST3 was significantly correlated with summed LBP and CST3 intensity scores in the glomerulus and peritubular capillary as well as Banff g + ptc scores. Urinary exosomal CST3 and LBP could be potent biomarkers for ABMR after kidney transplantation.
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Epstein, S., S. Ferrante, E. Nadler, M. Barberio, M. Golberg, L. Maltz, M. Hubal, and R. Freishtat. "17: OBESE ADIPOCYTE-DERIVED EXOSOMAL MIRNAS TARGETING TGF-β SIGNALING ARE ASSOCIATED WITH POOR ASTHMA CONTROL." Journal of Investigative Medicine 64, no. 3 (February 25, 2016): 813.2–814. http://dx.doi.org/10.1136/jim-2016-000080.33.
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Purpose of StudyObesity is a major risk factor for difficult-to-control asthma. We reported obese visceral adipose-derived exosomes contain miRNAs capable of impairing TGF-β signaling, a pathway involved in airway remodeling, associated with poor asthma clinical outcomes. We hypothesized that adipose-derived exosomal miRNAs from obese youth with asthma would be associated with poor asthma control.Methods UsedAsthMaP-2 Subjects (youth with physician-diagnosed asthma) were selected at extremes of obesity (n=10) and leanness (n=10). We profiled RNA from adipose-derived exosomes from serum and urine and identified significant correlations (p≤0.05) between obese adipose-derived exosomal miRNAs and Asthma Control Test (ACT) scores. Ingenuity Pathway Analysis generated predicted mRNA targets and pathways.Summary of ResultsObese subjects had a BMI≥98th percentile and lean subjects had a BMI≤13th percentile for age and sex. Serum adipose-derived exosomes contained 12 ACT-correlated miRNAs predicted to target 2,963 mRNAs with TGF-β Signaling as the top pathway (ratio=36/87; p=3×10−9). Urinary adipose-derived exosomes contained 7 ACT-correlated miRNAs predicted to target 2,387 mRNAs with TGF-β Signaling among the top pathways (ratio=18/87; p=0.01). The serum exosomal miRNAs were predicted to target TGF-β signaling mediators' mRNAs: downregulation of ACVR2B, SMAD3, SMAD5, and SMAD7 by miR-15a-5p (Fold Change (FC)=1.5; p=0.039) and upregulation of TGFB2 and TGFBR2 by miR-153-3p (FC=−1.7; p=0.041). The urinary exosomal miRNAs were also predicted to target TGF-β signaling mediators' mRNAs, the net effects were the opposite direction: upregulation of ACVR2B and SMAD4 by miR-138-5p (FC=−1.2; p=0.033) and downregulation of TGFB2 and TGFBR2 by miR-153-3p (FC=1.6; p=0.026) and SMAD6 by miR-3187-5p (FC=2.3; p=0.008).ConclusionsPoor asthma control in obese youth is associated with adipose-derived exosomal miRNAs in both serum and urine, in particular those that are predicted to affect TGF-β signaling. Due to anatomic considerations, visceral adipose-derived exosomes are expected to predominate in urine, while serum will contain a mix of both visceral and subcutaneous adipose-derived exosomes. Therefore, adipose-derived exosomes derived from urine may be useful biomarkers in obese subjects with asthma.
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Ramirez-Alvarado, Marina, Christopher J. Ward, Bing Q. Huang, Xun Gong, Marie C. Hogan, Benjamin J. Madden, Cristine Charlesworth, Angela Dispenzieri, Morie A. Gertz, and Nelson Leung. "Detection of High Molecular Weight Light Chain Oligomers in Urinary Exosomes of Patients with AL Amyloidosis." Blood 114, no. 22 (November 20, 2009): 4886. http://dx.doi.org/10.1182/blood.v114.22.4886.4886.
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Abstract Abstract 4886 Detection of high molecular weight light chain oligomers in urinary exosomes of patients with AL amyloidosis. Background Exosomes are microvesicles that are part of the multivesicular body (MVB) pathway. They are created by the inward budding of the cell surface membrane and contain both surface bound membrane proteins and cytosolic proteins which can be used to identify the cell of origin. Immunoglobulin light chain amyloidosis (AL) occurs as the result of amyloid formation by the misfolding of monoclonal light chains (LC) and deposition of these amyloid fibrils in various soft tissues. This reaction requires the organization of the monoclonal LC's into protofibrils which are then weave into amyloid fibrils. This study was undertaken to determine whether urinary exosomes of glomerular origin contain intermediate species of amyloid formation. Method Urine samples from patients with AL, light chain deposition disease (LCDD), multiple myeloma (MM) and monoclonal clonal gammopathy of undetermined significance (MGUS) were collected. Urinary exosomes were isolated and separated into fractions by gradient centrifugation. Western blots were performed on the urinary exosome fractions using anti-kappa or anti-lambda antibodies. Glomerular fractions were identified using antibodies directed toward podocin. Results Urine samples were collected from 5 patients with AL, 2 from LCDD, 1 from MM and 1 MGUS. On the Western blot, immunoglobulin LC were seen in all exosomal fractions in patients with AL amyloidosis, LCDD, MM but not MGUS which is similar to normal controls (not shown). In patients with AL, oligomeric species were found in the highest concentrations in fraction 4 and 5 (Figure 1). Fraction 4 and 5 were also stained for podocin, a glomerular protein (not shown). The highest molecular weight species was ∼250 kd which corresponds to a LC decamer. High molecular weight species were also identified in 1 of 2 LCDD patients corresponding to a tetramer. The band was identified in fraction 10 which had polycystin-1 expression suggesting a tubular origin. No high molecular weight LC species was found in patients with MM or MGUS. Conclusion Our study found high molecular weight LC species corresponding to the intermediates involved in protofibril formation in urinary exosomes of patients with AL. Smaller (tetramer) high molecular weight LC species were also found in a patient with LCDD but not in patients with MM and MGUS. Not only were the high molecular weight LC species found exclusively in the diseases characterized by deposition of LC aggregates, they were also found in the segments of the nephron where the deposits were expected: glomerulus for AL and tubular epithelium for LCDD. This is consistent with our current understanding of the pathogenic mechanisms of these diseases. We believe urinary exosomes are a powerful tool in the study of diseases involving self-aggregation of monoclonal proteins. It has tremendous potential in both diagnostic and scientific research in this area. Disclosures Gertz: celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Ni, Jianshu, Hongchao Li, Yiwen Zhou, Baojun Gu, Yuemin Xu, Qiang Fu, Xufeng Peng, et al. "Therapeutic Potential of Human Adipose-Derived Stem Cell Exosomes in Stress Urinary Incontinence – An in Vitro and in Vivo Study." Cellular Physiology and Biochemistry 48, no. 4 (2018): 1710–22. http://dx.doi.org/10.1159/000492298.
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Background/Aims: To evaluate whether local injection of exosomes derived from human adipose-derived stem cells (hADSCs) facilitates recovery of stress urinary incontinence (SUI) in a rat model. Methods: For the in vitro study, a Cell Counting Kit-8 (CCK-8) array and proteomic analysis were performed. For the in vivo study, female rats were divided into four groups: sham, SUI, adipose-derived stem cell (ADSC), and exosomes (n = 12 each). The SUI model was generated by pudendal nerve transection and vaginal dilation. Vehicle, hADSCs, or exosomes were injected into the peripheral urethra. After 2, 4, and 8 weeks, the rats underwent cystometrography and leak point pressure (LPP) testing, and tissues were harvested for histochemical analyses. Results: The CCK-8 experiment demonstrated that ADSC-derived exosomes could enhance the growth of skeletal muscle and Schwann cell lines in a dose-dependent manner. Proteomic analysis revealed that ADSC-derived exosomes contained various proteins of different signaling pathways. Some of these proteins are associated with the PI3K-Akt, Jak-STAT, and Wnt pathways, which are related to skeletal muscle and nerve regeneration and proliferation. In vivo experiments illustrated that rats of the exosome group had higher bladder capacity and LPP, and had more striated muscle fibers and peripheral nerve fibers in the urethra than rats of the SUI group. Both urethral function and histology of rats in the exosome group were slightly better than those in the ADSC group. Conclusions: Local injection of hADSC-derived exosomes improved functional and histological recovery after SUI.
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Lv, Lin-Li, Ye Feng, Yi Wen, Wei-Jun Wu, Hai-Feng Ni, Zuo-Lin Li, Le-Ting Zhou, et al. "Exosomal CCL2 from Tubular Epithelial Cells Is Critical for Albumin-Induced Tubulointerstitial Inflammation." Journal of the American Society of Nephrology 29, no. 3 (January 2, 2018): 919–35. http://dx.doi.org/10.1681/asn.2017050523.
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Albuminuria is a key instigator of tubulointerstitial inflammation associated with CKD, but the mechanism through which filtered albumin propagates renal injury remains unclear. In this study, we explored the role in this process of exosome mRNA released from tubular epithelial cells (TECs). Compared with control mice, acute and chronic kidney injury models had more exosomes containing inflammatory cytokine mRNA, particularly the chemokine CCL2, in kidneys and urine. In vitro stimulation of TECs with BSA recapitulated this finding. Notably, the internalization of purified TEC exosomes by cultured macrophages increased if TECs were exposed to BSA. Macrophage internalization of exosomes from BSA-treated TECs led to an enhanced inflammatory response and macrophage migration, but CCL2 silencing in TECs prevented these effects. Using a GFP-CCL2 fusion mRNA construct, we observed direct transfer of CCL2 mRNA from TEC exosomes to macrophages. Mice subjected to tail vein injection of purified BSA-treated TEC exosomes developed tubular injury with renal inflammatory cell infiltration. However, injection of exosomes from BSA-treated CCL2-deficient TECs induced less severe kidney inflammation. Finally, in patients with IgA nephropathy, the increase of proteinuria correlated with augmented urinary excretion of exosomes with exaggerated expression of CCL2 mRNA. Moreover, the level of CCL2 mRNA in urinary exosomes correlated closely with levels of renal interstitial macrophage infiltration in these patients. Our studies demonstrate that the increasing release of exosomes that transfer CCL2 mRNA from TECs to macrophages constitutes a critical mechanism of albumin-induced tubulointerstitial inflammation.
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Gudehithlu, Krishnamurthy P., Ignacio Garcia-Gomez, Jane Vernik, Carolyn Brecklin, Mark Kraus, David J. Cimbaluk, Peter Hart, George Dunea, Jose A. L. Arruda, and Ashok K. Singh. "In Diabetic Kidney Disease Urinary Exosomes Better Represent Kidney Specific Protein Alterations Than Whole Urine." American Journal of Nephrology 42, no. 6 (2015): 418–24. http://dx.doi.org/10.1159/000443539.
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Background: Predicting or diagnosing underlying kidney disease by analyzing whole urine remains the mainstay of nephrology practice. However, whole urine is a poor compartment to assess many structural changes in the kidney because whole urine contains only a few proteins derived from the kidney itself. Urinary exosomes, on the other hand, which are derived from the kidney, contain proteins secreted by the kidney. We experimentally tested the hypothesis that ‘urinary exosomes more faithfully represent changes in the kidney tissue than whole urine'. A direct comparison between whole urine and urine exosomal levels of two chosen kidney disease markers, gelatinase and ceruloplasmin, was carried out on diabetic kidney disease patients. Methods: Urinary exosomes were separated from whole urine by sequential centrifugation including ultra-centrifugation. Gelatinase activity was measured using fluorosceinated gelatin as the substrate, and ceruloplasmin was measured by sandwich ELISA. A few kidney specimens from patients biopsied for atypical features were histochemically stained for validation of the biochemical results. Results: We found that changes in both, gelatinase (decreased activity) and ceruloplasmin (increased levels), in the urinary exosomes of diabetic kidney patients were in agreement with the alterations of these two proteins in the kidney tissue. In contrast, the levels of these two proteins in whole urine were highly variable and did not correlate with levels in the diabetic kidney tissue. Conclusion: In conclusion, these results confirmed our hypothesis that protein markers in urinary exosomes better reflected the underlying protein changes in the kidney than in whole urine samples.
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Lv, Lin-Li, Yu-Han Cao, Hai-Feng Ni, Min Xu, Dan Liu, Hong Liu, Ping-Sheng Chen, and Bi-Cheng Liu. "MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis." American Journal of Physiology-Renal Physiology 305, no. 8 (October 15, 2013): F1220—F1227. http://dx.doi.org/10.1152/ajprenal.00148.2013.
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Micro (mi)RNAs are frequently dysregulated in the development of renal fibrosis. Exosomes are small membrane vesicles that could be isolated from urine secreted from all nephron segments. Here we sought to observe for the first time whether miRNA in urine exosome could serve as a potential biomarker of renal fibrosis. Urine samples were collected from 32 chronic kidney disease (CKD) patients who underwent kidney biopsy and 7 controls. Exosome was isolated and confirmed by immunogold staining of exosome marker. Members of miR-29, miR-200, and RNU6B as endogenous control were detected by RT quantitative PCR. Electronic microscopy verified a typical shape of exosome with average size of 65.1 nm and labeled it with anti-CD9 and anti-aquaporin 2 antibody. Members of miR-29 and miR-200 are readily measured with reduced levels compared with controls ( P < 0.05) and can robustly distinguish CKD from controls [area under the curve (AUC) varied from 0.902 to 1 by receiver operating characteristics analysis]. miR-29c correlated with both estimated glomerular filtration rate ( r = 0.362; P < 0.05) and degree of tubulointerstitial fibrosis ( r = −0.359; P < 0.05) for CKD patients. Moreover, miRNA in exosome was decreased in mild fibrosis group compared with moderated to severe group. miR-29a and miR-29c could predict degree of tubulointerstitial fibrosis with AUC of 0.883 and 0.738 ( P < 0.05). The sensitivity and specificity for distinguishing mild from moderate to severe fibrosis were 93.8 and 81.3% with the use of miR-29a and 68.8 and 81.3% for miR-29c. Overall, miR-29c in urinary exosome correlates with both renal function and degree of histological fibrosis, suggesting it as a novel, noninvasive marker for renal fibrosis.
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Xiong, Fangfang, Jiaxin Jia, Jiutong Ma, and Qiong Jia. "Glutathione-functionalized magnetic thioether-COFs for the simultaneous capture of urinary exosomes and enrichment of exosomal glycosylated and phosphorylated peptides." Nanoscale 14, no. 3 (2022): 853–64. http://dx.doi.org/10.1039/d1nr06587d.
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Solé, Moliné, Vidal, Ordi-Ros, and Cortés-Hernández. "An Exosomal Urinary miRNA Signature for Early Diagnosis of Renal Fibrosis in Lupus Nephritis." Cells 8, no. 8 (July 25, 2019): 773. http://dx.doi.org/10.3390/cells8080773.
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For lupus nephritis (LN) management, it is very important to detect fibrosis at an early stage. Urinary exosomal miRNAs profiling can be used as a potential multi-marker phenotyping tool to identify early fibrosis. We isolated and characterised urinary exosomes and cellular pellets from patients with biopsy-proven LN (n = 45) and healthy controls (n = 20). LN chronicity index (CI) correlated with urinary exosomal miR-21, miR-150, and miR-29c (r = 0.565, 0.840, −0.559, respectively). This miRNA profile distinguished low CI from moderate-high CI in LN patients with a high sensitivity and specificity (94.4% and 99.8%). Furthermore, this multimarker panel predicted an increased risk of progression to end-stage renal disease (ESRD). Pathway analysis identified VEGFA and SP1 as common target genes for the three miRNAs. Immunohistochemistry in LN renal biopsies revealed a significant increase of COL1A1 and COL4A1 correlated with renal chronicity. SP1 decreased significantly in the high-CI group (p = 0.002). VEGFA levels showed no differences. In vitro experiments suggest that these miRNA combinations promote renal fibrosis by increasing profibrotic molecules through SP1 and Smad3/TGFβ pathways. In conclusion, a urinary exosomal multimarker panel composed of miR-21, miR-150, and miR-29c provides a non-invasive method to detect early renal fibrosis and predict disease progression in LN.
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Bielopolski, Dana, Andrea Ronning, Dacia Vasquez, Glenis George-Alexander, Jeanne Walker, Jonathan N. Tobin, and Rhonda G. Kost. "4393 Translational Characterization of Blood Pressure Changes Following the DASH Diet– from Nutrition to Electrolytes to Exosomes." Journal of Clinical and Translational Science 4, s1 (June 2020): 41. http://dx.doi.org/10.1017/cts.2020.157.
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OBJECTIVES/GOALS: 1.analyze urinary protein exosome content pattern before and during DASH diet.2.characterize urine electrolyte changes associated with changes in protein profiles, and hormonal changes before/after DASH diet.3.analyze the association of these changes to the DASH-related BP response.METHODS/STUDY POPULATION: In this proof of concept study, hypertension stage 1 volunteers will receive a DASH based menu during 14 consecutive days of elective admission to the RU research hospital. Participants will complete a food frequency questionnaire (VioScreen) with a bionutritionist. Throughout the intervention period, participants will be assessed for blood pressure, plasma renin and aldosterone, and 24 hour urines for electrolytes, creatinine, protein, albumin and first morning urine collected for exosomes. Exosome analysis will be performed by a commercial lab. Proteome analysis will be conducted in the RU Mass-spectrometry service. RESULTS/ANTICIPATED RESULTS: The causal pathway we will elucidate hypothesizes that: 1) changes in diet affect blood electrolytes, and through these, aldosterone. 2) Aldosterone alters the expression of specific transporter proteins in the renal tubule; protein expression will be reflected in the urine exosome. 3) These transporters affect the excretion of electrolytes, as reflected by urinary ratio of sodium (Na) to Potassium (K). During consumption of the Western diet, the Na/K ratio is approximately 2-2.5, whereas we expect the urinary sodium/potassium ratio to be <1, when the participant is eating a DASH based diet. DISCUSSION/SIGNIFICANCE OF IMPACT: This assay provides a clinical tool to assess dietary adherence, and the project will provide insights into the mechanism whereby DASH reduces blood pressure.
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Du, Juan, Yihui Li, Qiang Sun, Zhihao Wang, Feng Wang, Fangfang Chen, Hao Wang, et al. "Urinary exosomal CD26 is associated with recovery from acute kidney injury in intensive care units: a prospective cohort study." Clinical Chemistry and Laboratory Medicine (CCLM) 59, no. 9 (April 22, 2021): 1535–46. http://dx.doi.org/10.1515/cclm-2021-0040.
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Abstract Objectives Currently there is no validated method to predict renal reversal and recovery after acute kidney injury (AKI). As exosomes have the potential for AKI prognosis and CD26 is involved in the mechanisms in AKI, this study aims to investigate whether urinary exosomal CD26 is associated with renal-related outcomes and explore its prospect as a novel prognosis biomarker. Methods This was a single-center, prospective cohort study. A total of 133 AKI patients and 68 non-AKI patients admitted to ICU in Qilu Hospital Shandong University from January 2017 to January 2018. Urine samples were collected at enrollment and the relative expression of CD26 (CD26 percentage) in urinary exosomes was examined, that was then categorized into a low-CD26 level and a high-CD26 level. Results CD26 percentage was significantly lower in the AKI cohort than in the control cohort. Within the AKI cohort, a high-CD26 level was associated with lower incidence of major adverse kidney events within 90 days, but higher incidence of reversal within 28 days. In AKI survivors, a high-CD26 level had a 4.67-, 3.50- and 4.66-fold higher odds than a low-CD26 level for early reversal, recovery and reversal, respectively, after adjustment for clinical factors. Prediction performance was moderate for AKI survivors but improved for non-septic AKI survivors. Conclusions Urinary exosomal CD26 is associated with renal reversal and recovery from AKI and is thus a promising prognosis biomarker.
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Zhang, Ning, Nianrong Sun, and Chunhui Deng. "A hydrophilic magnetic MOF for the consecutive enrichment of exosomes and exosomal phosphopeptides." Chemical Communications 56, no. 90 (2020): 13999–4002. http://dx.doi.org/10.1039/d0cc06147f.
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Choi, Hojun, Myung-Yoon Kim, Dae-Hwan Kim, Hanoul Yun, Byung-Koo Oh, Su-Bin Kim, In-Ho Song, et al. "Quantitative Biodistribution and Pharmacokinetics Study of GMP-Grade Exosomes Labeled with 89Zr Radioisotope in Mice and Rats." Pharmaceutics 14, no. 6 (May 24, 2022): 1118. http://dx.doi.org/10.3390/pharmaceutics14061118.
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For the successful clinical advancement of exosome therapeutics, the biodistribution and pharmacokinetic profile of exogenous exosomes in various animal models must be determined. Compared with fluorescence or bioluminescence imaging, radionuclide imaging confers multiple advantages for the in vivo tracking of biomolecular therapeutics because of its excellent sensitivity for deep tissue imaging and potential for quantitative measurement. Herein, we assessed the quantitative biodistribution and pharmacokinetics of good manufacturing practice-grade therapeutic exosomes labeled with zirconium-89 (89Zr) after systemic intravenous administration in mice and rats. Quantitative biodistribution analysis by positron emission tomography/computed tomography and gamma counting in mice and rats revealed that the total 89Zr signals in the organs were lower in rats than in mice, suggesting a higher excretion rate of exosomes in rats. A prolonged 89Zr signal for up to 7 days in most organs indicated that substantial amounts of exosomes were taken up by the parenchymal cells in those organs, highlighting the therapeutic potential of exosomes for the intracellular delivery of therapeutics. Exosomes were mainly distributed in the liver and to a lesser extent in the spleen, while a moderately distributed in the kidney, lung, stomach, intestine, urinary bladder, brain, and heart. Exosomes were rapidly cleared from the blood circulation, with a rate greater than that of free 89Zr, indicating that exosomes might be rapidly taken up by cells and tissues.
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Perez-Hernandez, Javier, Angela L. Riffo-Campos, Ana Ortega, Olga Martinez-Arroyo, Daniel Perez-Gil, Dolores Olivares, Elena Solaz, et al. "Urinary- and Plasma-Derived Exosomes Reveal a Distinct MicroRNA Signature Associated With Albuminuria in Hypertension." Hypertension 77, no. 3 (March 3, 2021): 960–71. http://dx.doi.org/10.1161/hypertensionaha.120.16598.
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Urinary albumin excretion (UAE) is a marker of cardiovascular risk and renal damage in hypertension. MicroRNAs (miRNAs) packaged into exosomes function as paracrine effectors in cell communication and the kidney is not exempt. This study aimed to state an exosomal miRNA profile/signature associated to hypertension with increased UAE and the impact of profibrotic TGF-β1 (transforming growth factor β1) on exosomes miRNA release. Therefore, exosomes samples from patients with hypertension with/without UAE were isolated and characterized. Three individual and unique small RNA libraries from each subject were prepared (total plasma, urinary, and plasma-derived exosomes) for next-generation sequencing profiling. Differentially expressed miRNAs were over-represented in Kyoto Encyclopedia of Genes and Genomes pathways, and selected miRNAs were validated by real-time quantitative polymerase chain reaction in a confirmation cohort. Thus, a signature of 29 dysregulated circulating miRNAs was identified in UAE hypertensive subjects, regulating 21 pathways. Moreover, changes in the levels of 4 exosomes-miRNAs were validated in a confirmation cohort and found associated with albuminuria. In particular miR-26a, major regulator of TGF-β signaling, was found downregulated in both type of exosomes when compared with healthy controls and to hypertension normoalbuminurics ( P <0.01). Similarly, decreased miR-26a levels were found in podocyte-derived exosomes after TGF-β stress. Our results revealed an exosomes miRNA signature associated to albuminuria in hypertension. In particular, exosomes miR-26a seemed to play a key role in the regulation of TGF-β, a relevant effector in podocyte damage. These findings support the use of exosomes miRNAs as biomarkers of cardiovascular risk progression and therapeutic tools in early kidney damage.
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Awdishu, Linda, Shirley Tsunoda, Michelle Pearlman, Chanthel Kokoy-Mondragon, Majid Ghassemian, Robert K. Naviaux, Heather M. Patton, Ravindra L. Mehta, Bhavya Vijay, and Satish P. RamachandraRao. "Identification of Maltase Glucoamylase as a Biomarker of Acute Kidney Injury in Patients with Cirrhosis." Critical Care Research and Practice 2019 (April 16, 2019): 1–8. http://dx.doi.org/10.1155/2019/5912804.
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Background. Acute kidney injury (AKI) is a frequent complication of decompensated cirrhosis with increased mortality. Traditional biomarkers such as serum creatinine are not sensitive for detecting injury without functional change. We hypothesize that urinary exosomes potentially carry markers that differentiate the type of kidney injury in cirrhotic patients. Methods. This is a prospective, single-center, and observational study of adult patients with cirrhosis. The patient groups included healthy normal controls, compensated cirrhosis with normal kidney function, decompensated cirrhosis with normal kidney function, and decompensated cirrhosis with AKI. Data were extracted from the electronic health record including etiology of liver disease, MELD score, history of decompensation, Child-Turcotte-Pugh score, history of AKI, and medication exposures. Urine samples were collected at the time of consent. Urine exosome protein content was analyzed, and proteomic data were validated by immunoblotting. Statistical analysis included partial least squares-discriminant analysis coupled with variable importance in projection identification. Results. Eighteen cirrhotic subjects were enrolled, and six healthy control subjects were extracted from our biorepository. Urine exosomes were isolated, and 1572 proteins were identified. Maltase-glucoamylase was the top discriminating protein confirmed by western blotting. Conclusions. Patients with cirrhosis and AKI have upregulation of renal brush border disaccharidase, MGAM, in urinary exosomes which may differentiate the type of kidney injury in cirrhosis; however, the clinical significance of this requires further validation.
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Liu, Yu-Ru, and Yi-Fen Lee. "Urinary exosome and beyond." Translational Cancer Research 5, S2 (August 2016): S321—S324. http://dx.doi.org/10.21037/tcr.2016.07.16.
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Dimov, Irena, Ljubinka Jankovic Velickovic, and Vladisav Stefanovic. "Urinary Exosomes." Scientific World JOURNAL 9 (2009): 1107–18. http://dx.doi.org/10.1100/tsw.2009.128.
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Exosomes are nanovesicles of endocytic origin that are secreted into the extracellular space or body fluids when a multivesicular body (MVB) fuses with the cell membrane. Interest in exosomes intensified after their description in antigen-presenting cells and the observation that they can significantly moderate immune responsesin vivo. In the past few years, several groups have reported on the secretion of exosomes by almost all cell types in an organism. In addition to a common set of membrane and cytosolic molecules, exosomes harbor unique subsets of proteins, reflecting their cellular source. Major research efforts were put into their surprisingly various biological functions and in translating knowledge into clinical practice. Urine provides an exciting noninvasive alternative to blood or tissue samples as a potential source of disease biomarkers. Urinary exosomes (UE) became the subject of serious studies just a few years ago. A recent large-scale proteomics-based study of normal UE revealed a myriad of proteins, including disease-related gene products. Thus, UE have valuable potential as a source of biomarkers for early detection of various types of diseases, monitoring the disease evolution and/or response to therapy. As a relatively new field of research, it still faces many challenges, but UE have already shown some straightforward potential.
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De Palma, Giuseppe, Vito Francesco Di Lorenzo, Silke Krol, and Angelo Virgilio Paradiso. "Urinary exosomal shuttle RNA: Promising cancer diagnosis biomarkers of lower urinary tract." International Journal of Biological Markers 34, no. 2 (March 13, 2019): 101–7. http://dx.doi.org/10.1177/1724600819827023.
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Background: Prostate and bladder cancers continue to be the first and fourth most common cancers in men worldwide; thus there is an urgent need for more accurate biomarkers that can detect these types of cancer in a non-invasive way. Liquid biopsy is a new non-invasive tool for diagnosis and with a virtually unlimited supply urine is even more attractive resource since urinary exosomes have been discovered to contain RNAs that are hallmarks of cancer. It is challenging to assay those secreting lower amounts of molecules. Methods: This review, based on articles identified through a PubMed/MEDLINE search, comprehensively summarizes state of the art approaches used in the discovery and validation of exosomal RNA biomarkers purified from the urine for lower urinary tract cancer. Results: The combination of PCA3 and ERG has shown a relatively good improvement in diagnostic performance; examples of other potential biomarkers and the methods utilized in their discovery are also discussed in this review. Conclusions: Of these last markers, to date there are still few data to implement these for routine diagnosis.
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Russo, Leileata M., Kendall Bate, Piruz Motamedinia, Guillermo Salazar, Anna Scott, Michael Lipsky, Neda Sadeghi, et al. "Urinary exosomes as a stable source of mRNA for prostate cancer analysis." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 174. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.174.
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174 Background: Exosomes are novel lipid bilayer vesicles that are released into biofluids such as urine and carry high integrity RNA from the parent cell which they were derived. Due to their unique stability and the fact that they contain prostate specific mRNA transcripts, we examined their potential as a non-invasive source of mRNA biomarkers for prostate cancer analysis. Methods: Following a Columbia University approved IRB protocol, random urine samples were collected from 163 men who were stratified into 4 groups: biopsy negative (Bx Neg, n=39), biopsy positive (Bx Pos, n=47), post-radical prostatectomy (RP, n=37) and controls (males <35 yrs, n=40). Urine samples were stored at 4°C and 0.8 μm filtration was used to remove whole cells and debris. Urinary exosomal RNA was isolated using our in-house technique. RT-qPCR was used to analyze PSA, PCA3, androgen receptor (AR), survivin, NCOA2, RAD21, transmembrane protease serine 2 (TMPRSS2), ERG and TMPRSS2:ERG fusion at the mRNA level. Results: Mean serum PSA protein level and age were similar in the Bx Neg and Bx Pos groups. Relative quantitation (RQ) of genes standardized to the PSA gene revealed that ERG (P<0.005), PCA3 (P<0.005), TMPRSS2:ERG fusion (P<0.05), TMPRSS2 (P<0.05) and survivin (P<0.005) were significantly increased in the Bx Pos vs. Bx Neg group. TMPRSS2:ERG fusion events occurred in 68% of Bx Pos vs. 44% of Bx Neg patients and were present in only 5% of controls. No patient in the RP group had positive TMPRSS2:ERG detection; this finding was further supported by the loss of TMPRSS2:ERG expression for 4 Bx Pos patients following prostatectomy suggesting specificity of the fusion event to the prostate. Conclusions: This study confirms urinary exosomes as a source of high quality RNA and showed significant differences in the expression of ERG, PCA3, TMPRSS2:ERG genes between the Bx Pos and Bx Neg groups. Our findings are consistent with previous studies based on tissue and post-prostate massage urinary cell analyses. The unique stability and yield of urinary exosomal RNA collected without a prostatic massage will hopefully simplify sample handing, obviate sample variability and patient discomfort inherent to prostate massage, and broaden the role of exosomes in future diagnostic testing.
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Walker, Jillian Marie, Padraic O’Malley, and Mei He. "Applications of Exosomes in Diagnosing Muscle Invasive Bladder Cancer." Pharmaceutics 14, no. 10 (September 23, 2022): 2027. http://dx.doi.org/10.3390/pharmaceutics14102027.
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Muscle Invasive Bladder Cancer (MIBC) is a subset of bladder cancer with a significant risk for metastases and death. It accounts for nearly 25% of bladder cancer diagnoses. A diagnostic work-up for MIBC is inclusive of urologic evaluation, radiographic imaging with a CT scan, urinalysis, and cystoscopy. These evaluations, especially cystoscopy, are invasive and carry the risk of secondary health concerns. Non-invasive diagnostics such as urine cytology are an attractive alternative currently being investigated to mitigate the requirement for cystoscopy. A pitfall in urine cytology is the lack of available options with high reliability, specificity, and sensitivity to malignant bladder cells. Exosomes are a novel biomarker source which could resolve some of the concerns with urine cytology, due to the high specificity as the surrogates of tumor cells. This review serves to define muscle invasive bladder cancer, current urine cytology methods, the role of exosomes in MIBC, and exosomes application as a diagnostic tool in MIBC. Urinary exosomes as the specific populations of extracellular vesicles could provide additional biomarkers with specificity and sensitivity to bladder malignancies, which are a consistent source of cellular information to direct clinicians for developing treatment strategies. Given its strong presence and differentiation ability between normal and cancerous cells, exosome-based urine cytology is highly promising in providing a perspective of a patient’s bladder cancer.
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Bruschi, Granata, Candiano, Fabris, Petretto, Ghiggeri, Gambaro, and Zaza. "Proteomic Analysis of Urinary Extracellular Vesicles Reveals a Role for the Complement System in Medullary Sponge Kidney Disease." International Journal of Molecular Sciences 20, no. 21 (November 5, 2019): 5517. http://dx.doi.org/10.3390/ijms20215517.
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Medullary sponge kidney (MSK) disease is a rare and neglected kidney condition often associated with nephrocalcinosis/nephrolithiasis and cystic anomalies in the precalyceal ducts. Little is known about the pathogenesis of this disease, so we addressed the knowledge gap using a proteomics approach. The protein content of microvesicles/exosomes isolated from urine of 15 MSK and 15 idiopathic calcium nephrolithiasis (ICN) patients was investigated by mass spectrometry, followed by weighted gene coexpression network analysis, support vector machine (SVM) learning, and partial least squares discriminant analysis (PLS-DA) to select the most discriminative proteins. Proteomic data were verified by ELISA. We identified 2998 proteins in total, 1764 (58.9%) of which were present in both vesicle types in both diseases. Among the MSK samples, only 65 (2.2%) and 137 (4.6%) proteins were exclusively found in the microvesicles and exosomes, respectively. Similarly, among the ICN samples, only 75 (2.5%) and 94 (3.1%) proteins were exclusively found in the microvesicles and exosomes, respectively. SVM learning and PLS-DA revealed a core panel of 20 proteins that distinguished extracellular vesicles representing each clinical condition with an accuracy of 100%. Among them, three exosome proteins involved in the lectin complement pathway maximized the discrimination between MSK and ICN: Ficolin 1, Mannan-binding lectin serine protease 2, and Complement component 4-binding protein β. ELISA confirmed the proteomic results. Our data show that the complement pathway is involved in the MSK, revealing a new range of potential therapeutic targets and early diagnostic biomarkers.
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Li, Yun, Jin Ji, Ji Lyu, Xin Jin, Xing He, Shaojia Mo, Huan Xu, et al. "A Novel Urine Exosomal lncRNA Assay to Improve the Detection of Prostate Cancer at Initial Biopsy: A Retrospective Multicenter Diagnostic Feasibility Study." Cancers 13, no. 16 (August 13, 2021): 4075. http://dx.doi.org/10.3390/cancers13164075.
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Purpose: This study aimed at developing and validating a novel noninvasive urinary exosome-based post-DRE (digital rectal examination) lncRNA assay to diagnose PCa (prostate cancer) and clinically significant PCa (Gleason score ≥ 7) from the initial prostate biopsy. Methods: A total of 602 urine samples from eligible participants were collected. The expression levels of urinary exosomal PCA3 (prostate cancer antigen 3) and MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) were detected by qPCR (quantitative real-time PCR). Receiver operating characteristic (ROC) analysis was applied to evaluate the diagnostic performance of PCA3, MALAT1 and the lncRNA assay. A decision curve analysis (DCA) and waterfall plots were used to assess the clinical value of the lncRNA assay. Results: Urinary exosomal PCA3 and MALAT1 were overexpressed in PCa and clinically significant PCa (p < 0.001). The lncRNA assay combining PCA3 and MALAT1 had a better diagnostic performance (AUC 0.828) than the current clinical parameters in detecting PCa. More importantly, the lncRNA assay yielded an AUC of 0.831 to detect clinically significant PCa, which is much higher than that of the current clinical parameters. The lncRNA assay was superior to PSA, f/tPSA and the base model for detecting PCa and clinically significant PCa, with a higher net benefit for almost all threshold probabilities. At the cutoff value of 95% sensitivity, the lncRNA assay could avoid 24.2% unnecessary biopsies while only missing 1.2% of the cases of clinically significant PCa. Conclusion: We developed and validated a novel noninvasive post-DRE urine-based lncRNA assay that presented good diagnostic power and clinical utility for the early diagnosis of PCa and high-grade PCa.
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Gauthier, Sebastien, Iwona Pranke, Vincent Jung, Loredana Martignetti, Véronique Stoven, Thao Nguyen-Khoa, Michaela Semeraro, et al. "Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease." International Journal of Molecular Sciences 21, no. 18 (September 10, 2020): 6625. http://dx.doi.org/10.3390/ijms21186625.
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Background: The prevalence of chronic kidney disease is increased in patients with cystic fibrosis (CF). The study of urinary exosomal proteins might provide insight into the pathophysiology of CF kidney disease. Methods: Urine samples were collected from 19 CF patients (among those 7 were treated by cystic fibrosis transmembrane conductance regulator (CFTR) modulators), and 8 healthy subjects. Urine exosomal protein content was determined by high resolution mass spectrometry. Results: A heatmap of the differentially expressed proteins in urinary exosomes showed a clear separation between control and CF patients. Seventeen proteins were upregulated in CF patients (including epidermal growth factor receptor (EGFR); proteasome subunit beta type-6, transglutaminases, caspase 14) and 118 were downregulated (including glutathione S-transferases, superoxide dismutase, klotho, endosomal sorting complex required for transport, and matrisome proteins). Gene set enrichment analysis revealed 20 gene sets upregulated and 74 downregulated. Treatment with CFTR modulators yielded no significant modification of the proteomic content. These results highlight that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity and that autophagy and endosomal targeting are impaired. Increased expression of EGFR and decreased expression of klotho and matrisome might play a central role in this CF kidney signature by inducing oxidation, inflammation, accelerated senescence, and abnormal tissue repair. Conclusions: Our study unravels novel insights into consequences of CFTR dysfunction in the urinary tract, some of which may have clinical and therapeutic implications.
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Asvapromtada, Siree, Hiroko Sonoda, Minami Kinouchi, Sayaka Oshikawa, Saki Takahashi, Yuya Hoshino, Thitaporn Sinlapadeelerdkul, Naoko Yokota-Ikeda, Toshiyuki Matsuzaki, and Masahiro Ikeda. "Characterization of urinary exosomal release of aquaporin-1 and -2 after renal ischemia-reperfusion in rats." American Journal of Physiology-Renal Physiology 314, no. 4 (April 1, 2018): F584—F601. http://dx.doi.org/10.1152/ajprenal.00184.2017.
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Acute kidney injury (AKI) is an important risk factor for the development of chronic kidney disease (CKD), and an alteration in renal water handling has been observed during the transition of AKI to CKD. Urinary exosomal release of aquaporin-1 (AQP1) and AQP2, important proteins for renal water handling, has recently been reported to predict their levels of renal expression. Therefore, we examined the patterns of urinary exosomal release of AQP1 and AQP2, and the exosomal marker proteins tumor susceptibility 101 protein (TSG101) and ALG-2 interacting protein X (Alix), in the acute and chronic phases following induction of AKI by renal bilateral ischemia/reperfusion (I/R) in rats. Blood tests and histological examinations indicated that AKI occurred before at 7 days after renal I/R ( day 7) and that renal fibrosis developed progressively thereafter. Immunoblotting demonstrated significant decreases in the urinary exosomal release of AQP1 and AQP2 during severe AKI. Urinary exosomal release of Alix and TSG101 was significantly increased on day 7. These data were also confirmed in rats with unilateral renal I/R causing more serious AKI. Urinary exosomal release of either the Ser-256- or Ser-269-phosphorylated form of AQP2, both of which are involved in apical trafficking of AQP2, was positively correlated with that of total AQP2. These results suggest that urinary exosomal release of AQP1 and AQP2 is reduced in I/R-induced AKI, whereas that of Alix and TSG101 is increased in the initial phase of renal fibrosis. Furthermore, apical trafficking of AQP2 appears to be related to urinary exosomal release of AQP2.
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Fenner, Annette. "Urinary exosome biomarkers of radiation exposure." Nature Reviews Urology 13, no. 8 (June 28, 2016): 437. http://dx.doi.org/10.1038/nrurol.2016.122.
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Valera, Vladimir, Beatriz Walter, and Maria J. Merino. "Abstract 5831: Urinary exosome analysis as a marker of treatment response in bladder cancer patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5831. http://dx.doi.org/10.1158/1538-7445.am2022-5831.
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Abstract Introduction: Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, BCG treatment failure will lead to recurrence and tumor progression. In this study, urinary exosomes content (miRNA profile) was evaluated as a possible marker of BCG treatment response in NMIBC patients. Methods: Urine samples from patients with bladder cancer were collected at the time of surgery and during patient follow up to 1 year. Urine from healthy volunteers were also included. Clinical and pathological information such as tumor grade (High Grade (HG), Low Grade (LG)), depth of invasion (Ta, T1, CIS), and response to BCG treatment was also obtained. Exosome Isolation and total RNA extraction including microRNAs from cell-free urine after centrifugation were obtained. Library preparation for miRNA expression was done (QIAseq® miRNA Library) for Next-Generation Sequencing (NGS) analysis in a NextSeq 2000 single read platform, 75 bp with 15-20 million reads per sample. Reads were then queried against miRDeep2 software for identification. Only miRNAs having at least 20 counts considering all samples were included. After normalization, significantly and deferentially expressed microRNAs (>2-Fold) were selected for analysis. Bioinformatic analysis including sequence alignment was performed under the STAR-based approach. Identified microRNAs were then used to classify/predict the response to treatment and its relationship with other clinicopathologic variables. Results: A total of 56 urine samples from 13 patients were available/used for analysis including 10 High Grade Ta and 3 High Grade T1 patients. Urine from normal healthy donors (N=3) was also included. Clinicopathological features were patients with HGTa=10, HGT1=3 and 3 control samples. Regarding treatment response 9 patients were BCG responders and 4 BCG unresponsive. When compared to BCG unresponsive patients, BCG responders showed 45 differentially expressed miRNAs. Statistically significant differentially expressed miRNAs (Fold-change >2, p value <0.05) were 12 miRNAs, upregulated were miR132-3p (p=0.042); miR-187-3p (p=0.021); miR-409-3p (p=0.043) and miR1301-3p (p=0.048). Downregulated miRNAs were miR-let7-5p (p=0.007), miR-3605-3p (p=0.047), miR-140-5p (p=0.031), miR-500a-5p (p=0.051), miR-629-5p (p=0.039), miR-454-3p (p=0.05), miR-2110 (p=0.049) and miR-30c-5p (p=0.03). Interestingly, miRPathDABv2.0 analysis predicted those microRNAs be related to cancer, including bladder cancer. They showed targeting important pathways as PI3K.Akt, Wnt/B catenin and P53 signaling related with disease progression and treatment response. Conclusion: Our study supports the value of urinary exosomal microRNAs as non-invasive biomarkers to predict BCG treatment response in nonmuscle-invasive bladder cancer. Citation Format: Vladimir Valera, Beatriz Walter, Maria J. Merino. Urinary exosome analysis as a marker of treatment response in bladder cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5831.
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Wang, Q., and S. Wang. "Quantitative proteomic analysis of urinary exosomes identifies S100 proteins as important exosomal biomarkers for nephrolithiasis." European Urology Open Science 19 (July 2020): e427. http://dx.doi.org/10.1016/s2666-1683(20)32848-2.
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Feng, Ye, Lin-Li Lv, Wei-Jun Wu, Zuo-Lin Li, Jun Chen, Hai-Feng Ni, Le-Ting Zhou, et al. "Urinary Exosomes and Exosomal CCL2 mRNA as Biomarkers of Active Histologic Injury in IgA Nephropathy." American Journal of Pathology 188, no. 11 (November 2018): 2542–52. http://dx.doi.org/10.1016/j.ajpath.2018.07.017.
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Sun, Ruihua, Huayuan Wang, Yingying Shi, Dandan Gao, Zhikun Sun, Zhongcan Chen, Haisong Jiang, and Jiewen Zhang. "A Pilot Study of Urinary Exosomes in Alzheimer’s Disease." Neurodegenerative Diseases 19, no. 5-6 (2019): 184–91. http://dx.doi.org/10.1159/000505851.
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Background: Exosomes are nano-sized extracellular vesicles secreted by most cell types and abundantly present in body fluids, including blood, saliva, urine, cerebrospinal fluid, and breast milk. Exosomes can spread toxic amyloid-beta (Aβ) and hyperphosphorylated tau between cells, contributing to neuronal loss in Alzheimer’s disease (AD). Objective: To explore changes in the morphology, number, and pathological protein levels of urinary exosomes in AD patients compared with age-matched healthy subjects. Methods: In this study, enzyme-linked immunosorbent assay was used to detect the levels of Aβ1–42 and P-S396-tau (normalized by CD63) in urinary exosomes of AD patients and matched healthy subjects. We used transmission electron microscopy and nanoparticle tracking analysis to observe the exosomes. Results: We found that the levels of Aβ1–42 and P-S396-tau in the urinary exosomes of AD patients were higher than those of matched healthy controls. Exosomes taken from AD patients were more numerous. Conclusion: The differences in levels of Aβ1–42 and P-S396-tau and the quantity of urinary exosomes between AD patients and healthy controls may provide a basis for early diagnosis of AD.
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Moon, Pyong‐Gon, Sungyong You, Jeong‐Eun Lee, Daehee Hwang, and Moon‐Chang Baek. "Urinary exosomes and proteomics." Mass Spectrometry Reviews 30, no. 6 (May 4, 2011): 1185–202. http://dx.doi.org/10.1002/mas.20319.
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Zhou, Hua, Hiroshi Kajiyama, Takayuki Tsuji, Xuzhen Hu, Asada Leelahavanichkul, Suzanne Vento, Rachel Frank, et al. "Urinary exosomal Wilms' tumor-1 as a potential biomarker for podocyte injury." American Journal of Physiology-Renal Physiology 305, no. 4 (August 15, 2013): F553—F559. http://dx.doi.org/10.1152/ajprenal.00056.2013.
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Renal Wilms' tumor-1 (WT-1) staining is used to detect podocyte loss in kidney biopsies. We aimed to determine if urinary exosomal WT-1 could serve as a noninvasive biomarker of podocyte injury. We examined WT-1 by Western blot in a human podocyte-like cell line, a mouse model of podocyte injury, and human subjects with podocyte disorders. WT-1 was detected in exosomal fraction of the conditioned media from podocytes and increased 48 h after hTGF-β1 stimulation. Cellular WT-1 decreased in podocytes following hTGF-β1 incubation. In mice with induced podocyte injury, urinary exosomal WT-1 was detected 1 wk earlier than albuminuria and also tracked the effects of angiotensin receptor blocker (ARB) treatment. In addition, urinary exosomal WT-1 levels at 1 wk post-injury correlated with the severity of glomerular injury at 3 wk later. In human subjects, urinary exosomal WT-1 was significantly increased in focal segmental glomerulosclerosis (FSGS) patients compared with healthy volunteers or steroid-sensitive nephrotic syndrome (SSNS) patients. Urinary exosomal WT-1 was also significantly decreased in patients in remission for either FSGS or SSNS or following steroid treatment in six SSNS subjects. We conclude that urinary exosomal WT-1 is a promising noninvasive biomarker with apparent podocyte specificity that can detect early progression and treatment-induced regression of podocyte injury in FSGS or SSNS. These results warrant longitudinal, prospective studies in a large cohort with a range of podocyte diseases.
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Shibata, Hirotaka. "Exosomes and exosomal cargo in urinary extracellular vesicles: novel potential biomarkers for mineralocorticoid-receptor-associated hypertension." Hypertension Research 44, no. 12 (October 1, 2021): 1668–70. http://dx.doi.org/10.1038/s41440-021-00759-2.
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