{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T04:00:29Z","timestamp":1792555229217,"version":"4.5.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:p>\n                    Novel therapies in autosomal dominant polycystic kidney disease (ADPKD) signal the need for markers of disease progression or response to therapy. This study aimed to identify disease-associated proteins in urinary extracellular vesicles (uEVs), which include exosomes, in patients with ADPKD. We performed quantitative proteomics on uEVs from healthy controls and patients with ADPKD using a labeled approach and then used a label-free approach with uEVs of different subjects (healthy controls versus patients with ADPKD versus patients with non-ADPKD CKD). In both experiments, 30 proteins were consistently more abundant (by two-fold or greater) in ADPKD-uEVs than in healthy- and CKD-uEVs. Of these proteins, we selected periplakin, envoplakin, villin-1, and complement C3 and C9 for confirmation because they were also significantly overrepresented in pathway analysis and were previously implicated in ADPKD pathogenesis. Immunoblotting confirmed higher abundances of the selected proteins in uEVs from three independent groups of patients with ADPKD. Whereas uEVs of young patients with ADPKD and preserved kidney function already had higher levels of complement, only uEVs of patients with advanced stages of ADPKD had increased levels of villin-1, periplakin, and envoplakin. Furthermore, all five proteins correlated positively with total kidney volume. Analysis in kidney tissue from mice with kidney-specific, tamoxifen-inducible\n                    <jats:italic toggle=\"yes\">Pkd1<\/jats:italic>\n                    deletion demonstrated higher expression in more severe stages of the disease and correlation with kidney weight for each protein of interest. In summary, proteomic analysis of uEVs identified plakins and complement as disease-associated proteins in ADPKD. These proteins are new candidates for evaluation as biomarkers or targets for therapy in ADPKD.\n                  <\/jats:p>","DOI":"10.1681\/asn.2015090994","type":"journal-article","created":{"date-parts":[[2016,9,30]],"date-time":"2016-09-30T13:23:40Z","timestamp":1475241820000},"page":"3079-3092","source":"Crossref","is-referenced-by-count":73,"title":["Proteomics of Urinary Vesicles Links Plakins and Complement to Polycystic Kidney Disease"],"prefix":"10.1681","volume":"27","author":[{"given":"Mahdi","family":"Salih","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology & Transplantation, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen A.","family":"Demmers","sequence":"additional","affiliation":[{"name":"Proteomics Center, Erasmus Medical Center, Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel","family":"Bezstarosti","sequence":"additional","affiliation":[{"name":"Proteomics Center, Erasmus Medical Center, Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter N.","family":"Leonhard","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"Losekoot","sequence":"additional","affiliation":[{"name":"Clinical Genetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cees","family":"van Kooten","sequence":"additional","affiliation":[{"name":"Nephrology, Leiden University Medical Center, Leiden, The Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron T.","family":"Gansevoort","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorien J.M.","family":"Peters","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Zietse","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology & Transplantation, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewout J.","family":"Hoorn","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology & Transplantation, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the DIPAK Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2016,3,3]]},"reference":[{"key":"B1-20231016","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1093\/ndt\/gfs551","article-title":"Epidemiology of autosomal-dominant polycystic kidney disease: An in-depth clinical study for south-western Germany.","volume":"28","author":"Neumann","year":"2013","journal-title":"Nephrol Dial Transplant"},{"key":"B2-20231016","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1016\/S0140-6736(15)60907-2","article-title":"Autosomal dominant polycystic kidney disease: The changing face of clinical management.","volume":"385","author":"Ong","year":"2015","journal-title":"Lancet"},{"key":"B3-20231016","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3402\/jev.v2i0.20389","article-title":"As we wait: Coping with an imperfect nomenclature for extracellular vesicles.","volume":"2","author":"Gould","year":"2013","journal-title":"J Extracell Vesicles"},{"key":"B4-20231016","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1002\/pmic.201200285","article-title":"Urinary exosomes: A reservoir for biomarker discovery and potential mediators of intrarenal signalling.","volume":"13","author":"Dear","year":"2013","journal-title":"Proteomics"},{"key":"B5-20231016","doi-asserted-by":"crossref","first-page":"F1251","DOI":"10.1152\/ajprenal.00128.2014","article-title":"Urinary extracellular vesicles and the kidney: Biomarkers and beyond.","volume":"306","author":"Salih","year":"2014","journal-title":"Am J Physiol Renal Physiol"},{"key":"B6-20231016","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1038\/ki.2011.292","article-title":"Exosomes and the kidney: Prospects for diagnosis and therapy of renal diseases.","volume":"80","author":"van Balkom","year":"2011","journal-title":"Kidney Int"},{"key":"B7-20231016","doi-asserted-by":"crossref","first-page":"13368","DOI":"10.1073\/pnas.0403453101","article-title":"Identification and proteomic profiling of exosomes in human urine.","volume":"101","author":"Pisitkun","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B8-20231016","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1161\/HYPERTENSIONAHA.112.198135","article-title":"The phosphorylated sodium chloride cotransporter in urinary exosomes is superior to prostasin as a marker for aldosteronism.","volume":"60","author":"van der Lubbe","year":"2012","journal-title":"Hypertension"},{"key":"B9-20231016","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/ki.1996.387","article-title":"Role of obstruction in autosomal dominant polycystic kidney disease in rats.","volume":"50","author":"Tanner","year":"1996","journal-title":"Kidney Int"},{"key":"B10-20231016","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1038\/ki.1987.121","article-title":"Cyst formation and growth in autosomal dominant polycystic kidney disease.","volume":"31","author":"Grantham","year":"1987","journal-title":"Kidney Int"},{"key":"B11-20231016","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1681\/ASN.2008060564","article-title":"Characterization of PKD protein-positive exosome-like vesicles.","volume":"20","author":"Hogan","year":"2009","journal-title":"J Am Soc Nephrol"},{"key":"B13-20231016","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/prca.201100108","article-title":"Application of systems biology principles to protein biomarker discovery: Urinary exosomal proteome in renal transplantation.","volume":"6","author":"Pisitkun","year":"2012","journal-title":"Proteomics Clin Appl"},{"key":"B14-20231016","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/gb-2003-4-5-p3","article-title":"DAVID: Database for Annotation, Visualization, and Integrated Discovery.","volume":"4","author":"Dennis","year":"2003","journal-title":"Genome Biol"},{"key":"B15-20231016","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1111\/joim.12307","article-title":"Complement C3 activation in cyst fluid and urine from autosomal dominant polycystic kidney disease patients.","volume":"276","author":"Mrug","year":"2014","journal-title":"J Intern Med"},{"key":"B16-20231016","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/sj.ki.5002627","article-title":"Overexpression of innate immune response genes in a model of recessive polycystic kidney disease.","volume":"73","author":"Mrug","year":"2008","journal-title":"Kidney Int"},{"key":"B17-20231016","doi-asserted-by":"crossref","first-page":"F1153","DOI":"10.1152\/ajprenal.00008.2005","article-title":"Mispolarization of desmosomal proteins and altered intercellular adhesion in autosomal dominant polycystic kidney disease.","volume":"288","author":"Silberberg","year":"2005","journal-title":"Am J Physiol Renal Physiol"},{"key":"B18-20231016","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1111\/joim.12214","article-title":"Excessive activation of the alternative complement pathway in autosomal dominant polycystic kidney disease.","volume":"276","author":"Su","year":"2014","journal-title":"J Intern Med"},{"key":"B19-20231016","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1093\/hmg\/9.18.2743","article-title":"Polycystin-1, the product of the polycystic kidney disease 1 gene, co-localizes with desmosomes in MDCK cells.","volume":"9","author":"Scheffers","year":"2000","journal-title":"Hum Mol Genet"},{"key":"B20-20231016","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/ki.2009.550","article-title":"Tamm-Horsfall protein and urinary exosome isolation.","volume":"77","author":"Fern\u00e1ndez-Llama","year":"2010","journal-title":"Kidney Int"},{"key":"B22-20231016","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1681\/ASN.2005030322","article-title":"Combined proteomics and pathways analysis of collecting duct reveals a protein regulatory network activated in vasopressin escape.","volume":"16","author":"Hoorn","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"B23-20231016","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1093\/hmg\/ddm299","article-title":"Kidney-specific inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice.","volume":"16","author":"Lantinga-van Leeuwen","year":"2007","journal-title":"Hum Mol Genet"},{"key":"B24-20231016","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1093\/ndt\/gfr069","article-title":"Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: Optimal timing and dosing of the drug.","volume":"26","author":"Meijer","year":"2011","journal-title":"Nephrol Dial Transplant"},{"key":"B25-20231016","doi-asserted-by":"crossref","first-page":"F1193","DOI":"10.1152\/ajprenal.00419.2010","article-title":"Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways: In vivo evidence from a Pkd1-deletion model.","volume":"300","author":"Leonhard","year":"2011","journal-title":"Am J Physiol Renal Physiol"},{"key":"B26-20231016","first-page":"31972","article-title":"Interaction of phospholipase C-gamma1 with villin regulates epithelial cell migration.","volume":"281","author":"Tomar","year":"2006","journal-title":"J Biol Chem"},{"key":"B27-20231016","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s12860-015-0059-3","article-title":"Regulation of the microtubular cytoskeleton by Polycystin-1 favors focal adhesions turnover to modulate cell adhesion and migration.","volume":"16","author":"Castelli","year":"2015","journal-title":"BMC Cell Biol"},{"key":"B28-20231016","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1038\/ncomms3658","article-title":"Polycystin-1 binds Par3\/aPKC and controls convergent extension during renal tubular morphogenesis.","volume":"4","author":"Castelli","year":"2013","journal-title":"Nat Commun"},{"key":"B29-20231016","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/S0272-6386(12)80338-6","article-title":"Aberrant epithelial cell growth in autosomal dominant polycystic kidney disease.","volume":"17","author":"Wilson","year":"1991","journal-title":"Am J Kidney Dis"},{"key":"B30-20231016","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nrm1425","article-title":"Plakins: Goliaths that link cell junctions and the cytoskeleton.","volume":"5","author":"Jefferson","year":"2004","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B31-20231016","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1172\/JCI5111","article-title":"Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins.","volume":"104","author":"Huan","year":"1999","journal-title":"J Clin Invest"},{"key":"B32-20231016","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1002\/prca.200800163","article-title":"The biomarker enriched proteome of autosomal dominant polycystic kidney disease cyst fluid.","volume":"3","author":"Mason","year":"2009","journal-title":"Proteomics Clin Appl"},{"key":"B33-20231016","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1002\/prca.200780140","article-title":"Characterization of the renal cyst fluid proteome in autosomal dominant polycystic kidney disease (ADPKD) patients.","volume":"2","author":"Lai","year":"2008","journal-title":"Proteomics Clin Appl"},{"key":"B34-20231016","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1038\/ki.2013.422","article-title":"Subfractionation, characterization, and in-depth proteomic analysis of glomerular membrane vesicles in human urine.","volume":"85","author":"Hogan","year":"2014","journal-title":"Kidney Int"},{"key":"B35-20231016","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1681\/ASN.2008040406","article-title":"Large-scale proteomics and phosphoproteomics of urinary exosomes.","volume":"20","author":"Gonzales","year":"2009","journal-title":"J Am Soc Nephrol"},{"key":"B36-20231016","doi-asserted-by":"crossref","first-page":"546","DOI":"10.4049\/jimmunol.143.2.546","article-title":"Transcellular transport and membrane insertion of the C5b-9 membrane attack complex of complement by glomerular epithelial cells in experimental membranous nephropathy.","volume":"143","author":"Kerjaschki","year":"1989","journal-title":"J Immunol"},{"key":"B37-20231016","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1681\/ASN.2012111064","article-title":"Cyclosporine induces endothelial cell release of complement-activating microparticles.","volume":"24","author":"Renner","year":"2013","journal-title":"J Am Soc Nephrol"},{"key":"B38-20231016","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.4049\/jimmunol.1402470","article-title":"Shiga toxin-induced complement-mediated hemolysis and release of complement-coated red blood cell-derived microvesicles in hemolytic uremic syndrome.","volume":"194","author":"Arvidsson","year":"2015","journal-title":"J Immunol"},{"key":"B39-20231016","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1093\/ndt\/15.10.1506","article-title":"Is there a role for locally produced complement in renal disease?","volume":"15","author":"Daha","year":"2000","journal-title":"Nephrol Dial Transplant"},{"key":"B40-20231016","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1681\/ASN.2013101066","article-title":"Human urinary exosomes as innate immune effectors.","volume":"25","author":"Hiemstra","year":"2014","journal-title":"J Am Soc Nephrol"},{"key":"B41-20231016","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.molimm.2007.07.037","article-title":"The classical complement pathway plays a critical role in the opsonisation of uropathogenic Escherichia coli.","volume":"45","author":"Li","year":"2008","journal-title":"Mol Immunol"},{"key":"B42-20231016","doi-asserted-by":"crossref","DOI":"10.1681\/ASN.2014040354","article-title":"Identification of biomarkers for PKD1 using urinary exosomes.","author":"Hogan","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"B43-20231016","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1111\/j.1523-1755.2002.kid565.x","article-title":"Proteomic analysis of normal human urinary proteins isolated by acetone precipitation or ultracentrifugation.","volume":"62","author":"Thongboonkerd","year":"2002","journal-title":"Kidney Int"},{"key":"B44-20231016","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1097\/01.ASN.0000129114.92265.32","article-title":"Discovery of protein biomarkers for renal diseases.","volume":"15","author":"Hewitt","year":"2004","journal-title":"J Am Soc Nephrol"},{"key":"B45-20231016","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1053\/j.ajkd.2013.10.011","article-title":"Rationale and design of the DIPAK 1 study: a randomized controlled clinical trial assessing the efficacy of lanreotide to halt disease progression in autosomal dominant polycystic kidney disease.","volume":"63","author":"Meijer","year":"2014","journal-title":"Am J Kidney Dis"},{"key":"B46-20231016","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1681\/ASN.2011101032","article-title":"Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing.","volume":"23","author":"Rossetti","year":"2012","journal-title":"J Am Soc Nephrol"},{"key":"B47-20231016","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1038\/ki.2012.256","article-title":"Comparison of protein, microRNA, and mRNA yields using different methods of urinary exosome isolation for the discovery of kidney disease biomarkers.","volume":"82","author":"Alvarez","year":"2012","journal-title":"Kidney Int"},{"key":"B48-20231016","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.ymeth.2013.03.031","article-title":"Quantitative comparison of the fasted and re-fed mouse liver phosphoproteomes using lower pH reductive dimethylation.","volume":"61","author":"Wilson-Grady","year":"2013","journal-title":"Methods"},{"key":"B49-20231016","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nbt.2839","article-title":"ProteomeXchange provides globally coordinated proteomics data submission and dissemination.","volume":"32","author":"Vizca\u00edno","year":"2014","journal-title":"Nat Biotechnol"},{"key":"B50-20231016","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1038\/nbt.1511","article-title":"MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification.","volume":"26","author":"Cox","year":"2008","journal-title":"Nat Biotechnol"},{"key":"B51-20231016","doi-asserted-by":"crossref","first-page":"9819","DOI":"10.1021\/ac901335x","article-title":"Software tool for researching annotations of proteins: open-source protein annotation software with data visualization.","volume":"81","author":"Bhatia","year":"2009","journal-title":"Anal Chem"},{"key":"B52-20231016","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jim.2015.02.010","article-title":"Functional assessment of mouse complement pathway activities and quantification of C3b\/C3c\/iC3b in an experimental model of mouse renal ischaemia\/reperfusion injury.","volume":"419","author":"Kotimaa","year":"2015","journal-title":"J Immunol Methods"}],"container-title":["Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/00001751-201610000-00019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:28:19Z","timestamp":1786130899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/00001751-201610000-00019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,3]]},"references-count":50,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2016]]}},"URL":"https:\/\/doi.org\/10.1681\/asn.2015090994","relation":{},"ISSN":["1046-6673","1533-3450"],"issn-type":[{"value":"1046-6673","type":"print"},{"value":"1533-3450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,3]]}}}