{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T20:16:40Z","timestamp":1787861800044,"version":"build-2784847793"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T00:00:00Z","timestamp":1589846400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T00:00:00Z","timestamp":1589846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The polymeric immunoglobulin receptor (pIgR) transports immunoglobulins from the basolateral to the apical surface of epithelial cells. PIgR was recently shown to be associated with kidney dysfunction. The immune defense is initiated at the apical surface of epithelial cells where the N-terminal domain of pIgR, termed secretory component (SC), is proteolytically cleaved and released either unbound (free SC) or bound to immunoglobulins. The aim of our study was to evaluate the association of pIgR peptides with the cardio-renal syndrome in a large cohort and to obtain information on how the SC is released. We investigated urinary peptides of 2964 individuals available in the Human Urine Proteome Database generated using capillary electrophoresis coupled to mass spectrometry. The mean amplitude of 23 different pIgR peptides correlated negatively with the estimated glomerular filtration rate (eGFR, rho\u2009=\u2009\u22120.309, p\u2009&lt;\u20090.0001). Furthermore, pIgR peptides were significantly increased in cardiovascular disease (coronary artery disease and heart failure) after adjustment for eGFR. We further predicted potential proteases involved in urinary peptide generation using the Proteasix algorithm. Peptide cleavage site analysis suggested that several, and not one, proteases are involved in the generation of the SC. In this large cohort, we could demonstrate that pIgR is associated with the cardio-renal syndrome and provided a more detailed insight on how pIgR can be potentially cleaved to release the SC.<\/jats:p>","DOI":"10.1038\/s41598-020-65154-2","type":"journal-article","created":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T10:04:11Z","timestamp":1589882651000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Associations of urinary polymeric immunoglobulin receptor peptides in the context of cardio-renal syndrome"],"prefix":"10.1038","volume":"10","author":[{"given":"Tianlin","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Siwy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Metzger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Mullen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Mischak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost P.","family":"Schanstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Z\u00fcrbig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Jankowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,19]]},"reference":[{"key":"65154_CR1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/S1471-4906(02)00031-5","volume":"24","author":"A Phalipon","year":"2003","unstructured":"Phalipon, A. & Corthesy, B. Novel functions of the polymeric Ig receptor: well beyond transport of immunoglobulins. Trends Immunol. 24, 55\u201358 (2003).","journal-title":"Trends Immunol."},{"key":"65154_CR2","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/308037a0","volume":"308","author":"KE Mostov","year":"1984","unstructured":"Mostov, K. E., Friedlander, M. & Blobel, G. The receptor for transepithelial transport of IgA and IgM contains multiple immunoglobulin-like domains. Nature 308, 37\u201343 (1984).","journal-title":"Nature"},{"key":"65154_CR3","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.4049\/jimmunol.154.4.1735","volume":"154","author":"JF Piskurich","year":"1995","unstructured":"Piskurich, J. F., Blanchard, M. H., Youngman, K. R., France, J. A. & Kaetzel, C. S. Molecular cloning of the mouse polymeric Ig receptor. Functional regions of the molecule are conserved among five mammalian species. J Immunol. 154, 1735\u20131747 (1995).","journal-title":"J Immunol."},{"key":"65154_CR4","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1111\/j.0105-2896.2005.00278.x","volume":"206","author":"CS Kaetzel","year":"2005","unstructured":"Kaetzel, C. S. The polymeric immunoglobulin receptor: bridging innate and adaptive immune responses at mucosal surfaces. Immunol. Rev. 206, 83\u201399 (2005).","journal-title":"Immunol. Rev."},{"key":"65154_CR5","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1515\/bchm2.1984.365.2.1489","volume":"365","author":"H Eiffert","year":"1984","unstructured":"Eiffert, H. et al. [The primary structure of human free secretory component and the arrangement of disulfide bonds]. Hoppe Seylers. Z. Physiol Chem. 365, 1489\u20131495 (1984).","journal-title":"Hoppe Seylers. Z. Physiol Chem."},{"key":"65154_CR6","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/0378-1119(95)00520-G","volume":"164","author":"MP Verbeet","year":"1995","unstructured":"Verbeet, M. P., Vermeer, H., Warmerdam, G. C., de Boer, H. A. & Lee, S. H. Cloning and characterization of the bovine polymeric immunoglobulin receptor-encoding cDNA. Gene 164, 329\u2013333 (1995).","journal-title":"Gene"},{"key":"65154_CR7","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1016\/j.ajpath.2019.06.015","volume":"189","author":"KM Krawczyk","year":"2019","unstructured":"Krawczyk, K. M. et al. Localization and Regulation of Polymeric Ig Receptor in Healthy and Diseased Human Kidney. Am J Pathol. 189, 1933\u20131944 (2019).","journal-title":"Am J Pathol."},{"key":"65154_CR8","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1177\/2048872612471212","volume":"2","author":"HV de","year":"2013","unstructured":"de, H. V. et al. Serum extracellular vesicle protein levels are associated with acute coronary syndrome. Eur. Heart J Acute. Cardiovasc. Care 2, 53\u201360 (2013).","journal-title":"Eur. Heart J Acute. Cardiovasc. Care"},{"key":"65154_CR9","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/0021-9150(88)90204-3","volume":"74","author":"A Muscari","year":"1988","unstructured":"Muscari, A. et al. Association of serum IgA and C4 with severe atherosclerosis. Atherosclerosis 74, 179\u2013186 (1988).","journal-title":"Atherosclerosis"},{"key":"65154_CR10","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1159\/000175995","volume":"83","author":"A Muscari","year":"1993","unstructured":"Muscari, A. et al. Increased serum IgA levels in subjects with previous myocardial infarction or other major ischemic events. Cardiology 83, 383\u2013389 (1993).","journal-title":"Cardiology"},{"key":"65154_CR11","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1002\/elps.201900091","volume":"40","author":"A Latosinska","year":"2019","unstructured":"Latosinska, A., Siwy, J., Mischak, H. & Frantzi, M. Peptidomics and proteomics based on CE-MS as a robust tool in clinical application: The past, the present, and the future. Electrophoresis 40, 2294\u20132308 (2019).","journal-title":"Electrophoresis"},{"key":"65154_CR12","doi-asserted-by":"crossref","unstructured":"Klein, J. et al. Proteasix: A tool for automated and large-scale prediction of proteases involved in naturally-occurring peptide generation. 13, 1077\u20131082 (2013).","DOI":"10.1002\/pmic.201200493"},{"key":"65154_CR13","first-page":"1510","volume":"32","author":"C Pontillo","year":"2016","unstructured":"Pontillo, C. et al. A urinary proteome-based classifier for the early detection of decline in glomerular filtration. Nephrol. Dial. Transplant. 32, 1510\u20131516 (2016).","journal-title":"Nephrol. Dial. Transplant."},{"key":"65154_CR14","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1093\/ckj\/sfx002","volume":"10","author":"C Pontillo","year":"2017","unstructured":"Pontillo, C. & Mischak, H. Urinary peptide-based classifier CKD273: towards clinical application in chronic kidney disease. Clin. Kidney J. 10, 192\u2013201 (2017).","journal-title":"Clin. Kidney J."},{"key":"65154_CR15","first-page":"35","volume":"14","author":"H Ben-Hur","year":"2004","unstructured":"Ben-Hur, H. et al. Secretory immune system in human embryonic and fetal development: joining chain and immunoglobulin transport (Review). Int J Mol. Med. 14, 35\u201342 (2004).","journal-title":"Int J Mol. Med."},{"key":"65154_CR16","doi-asserted-by":"publisher","first-page":"e0173880","DOI":"10.1371\/journal.pone.0173880","volume":"12","author":"CK Ward-Caviness","year":"2017","unstructured":"Ward-Caviness, C. K. et al. A genome-wide trans-ethnic interaction study links the PIGR-FCAMR locus to coronary atherosclerosis via interactions between genetic variants and residential exposure to traffic. PLoS. ONE. 12, e0173880 (2017).","journal-title":"PLoS. ONE."},{"key":"65154_CR17","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1111\/sji.12093","volume":"78","author":"K Sunagawa","year":"2013","unstructured":"Sunagawa, K. et al. Distinct functional regions of the human polymeric immunoglobulin receptor. Scand. J Immunol. 78, 339\u2013344 (2013).","journal-title":"Scand. J Immunol."},{"key":"65154_CR18","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/S0014-5793(97)00629-7","volume":"410","author":"GJ Hughes","year":"1997","unstructured":"Hughes, G. J. et al. Human free secretory component is composed of the first 585 amino acid residues of the polymeric immunoglobulin receptor. FEBS Lett. 410, 443\u2013446 (1997).","journal-title":"FEBS Lett."},{"key":"65154_CR19","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1111\/j.1365-2567.2004.01914.x","volume":"112","author":"M Asano","year":"2004","unstructured":"Asano, M. et al. Multiple cleavage sites for polymeric immunoglobulin receptor. Immunology 112, 583\u2013589 (2004).","journal-title":"Immunology"},{"key":"65154_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15359-9","volume":"7","author":"M Krochmal","year":"2017","unstructured":"Krochmal, M. et al. Urinary peptidomics analysis reveals proteases involved in diabetic nephropathy. Sci. Rep. 7, 15160 (2017).","journal-title":"Sci. Rep."},{"key":"65154_CR21","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1089\/wound.2012.0370","volume":"2","author":"SM McCarty","year":"2013","unstructured":"McCarty, S. M. & Percival, S. L. Proteases and Delayed Wound Healing. Adv. Wound. Care (New Rochelle.) 2, 438\u2013447 (2013).","journal-title":"Adv. Wound. Care (New Rochelle.)"},{"key":"65154_CR22","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/j.kint.2015.10.010","volume":"89","author":"J Klein","year":"2016","unstructured":"Klein, J., Bascands, J. L., Mischak, H. & Schanstra, J. P. The role of urinary peptidomics in kidney disease research. Kidney Int. 89, 539\u2013545 (2016).","journal-title":"Kidney Int."},{"key":"65154_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17083-w","volume":"7","author":"P Magalh\u00e3es","year":"2017","unstructured":"Magalh\u00e3es, P. et al. Association of kidney fibrosis with urinary peptides: a path towards non-invasive liquid biopsies? Sci. Rep. 7, 16915 (2017).","journal-title":"Sci. Rep."},{"key":"65154_CR24","doi-asserted-by":"publisher","first-page":"2316","DOI":"10.1097\/HJH.0b013e32833d81b7","volume":"28","author":"C Delles","year":"2010","unstructured":"Delles, C. et al. Urinary proteomic diagnosis of coronary artery disease: identification and clinical validation in 623 individuals. J. Hypertens. 28, 2316\u20132322 (2010).","journal-title":"J. Hypertens."},{"key":"65154_CR25","first-page":"163","volume":"6","author":"CF Zhao","year":"2016","unstructured":"Zhao, C. F. & Herrington, D. M. The function of cathepsins B, D, and X in atherosclerosis. Am J Cardiovasc. Dis. 6, 163\u2013170 (2016).","journal-title":"Am J Cardiovasc. Dis."},{"key":"65154_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/srep20101","volume":"6","author":"C Fox","year":"2016","unstructured":"Fox, C. et al. Inhibition of lysosomal protease cathepsin D reduces renal fibrosis in murine chronic kidney disease. Sci. Rep 6, 20101 (2016).","journal-title":"Sci. Rep"},{"key":"65154_CR27","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1001\/jama.2013.281053","volume":"310","author":"World Medical Association","year":"2013","unstructured":"World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310, 2191\u20132194 (2013).","journal-title":"JAMA"},{"key":"65154_CR28","doi-asserted-by":"publisher","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","volume":"150","author":"AS Levey","year":"2009","unstructured":"Levey, A. S. et al. A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 150, 604\u2013612 (2009).","journal-title":"Ann. Intern. Med."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65154-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65154-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65154-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T08:13:02Z","timestamp":1696147982000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65154-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,19]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["65154"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-65154-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,19]]},"assertion":[{"value":"17 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Harald Mischak is the founder and co-owner of Mosaiques Diagnostics GmbH. Tianlin He, Justyna Siwy, Jochen Metzger, and Petra Z\u00fcrbig are employed by Mosaiques Diagnostics GmbH. All other authors do not have any competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8291"}}