{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:01:36Z","timestamp":1786132896436,"version":"build-2736575974"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["322900939"],"award-info":[{"award-number":["322900939"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2021,12]]},"abstract":"\n Significance Statement<\/jats:title>\n Posttranslational guanidinylation of ApoC3, a major constituent of triglyceride-rich lipoproteins, enhances ApoC3\u2032s proinflammatory properties in uremia. Guanidinylated ApoC3 (gApoC3) is generated by guanidine and urea, and accumulates significantly in the plasma of patients with CKD, and in the kidneys of mouse models of CKD. In humanized mice, gApoC3 promotes kidney tissue fibrosis and suppresses regeneration after vascular injury. Importantly, in a large observational trial examining the clinical relevance of this posttranslational modification in patients with CKD, higher plasma gApoC3 intensity was associated with adverse renal and cardiovascular outcomes. Therefore, gApoC3 represents a novel mediator of kidney injury and CKD-associated vascular disease and offers a potential treatment target to halt progression and to prevent vascular disease in patients with CKD.<\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n Coexistent CKD and cardiovascular diseases are highly prevalent in Western populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response\n in vitro,<\/jats:italic>\n as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 in monocytes\n in vitro<\/jats:italic>\n . In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2021040503","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T14:13:17Z","timestamp":1632924797000},"page":"3146-3160","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":28,"title":["Guanidinylated Apolipoprotein C3 (ApoC3) Associates with Kidney and Vascular Injury"],"prefix":"10.1681","volume":"32","author":[{"given":"Stefan J.","family":"Schunk","sequence":"first","affiliation":[{"name":"Nephrology and Hypertension, Department of Internal Medicine IV, Saarland University, Homburg\/Saar, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Hermann","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cardiovascular Research, RWTH Aachen University Hospital, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamim","family":"Sarakpi","sequence":"additional","affiliation":[{"name":"Nephrology and Hypertension, Department of Internal Medicine IV, Saarland University, Homburg\/Saar, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Triem","sequence":"additional","affiliation":[{"name":"Translational Cardio-Renal Medicine, Saarland University, Homburg\/Saar, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8300-4183","authenticated-orcid":false,"given":"Michaela","family":"Lellig","sequence":"additional","affiliation":[{"name":"Institute of Molecular 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Homburg\/Saar, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"M\u00f6llmann","sequence":"additional","affiliation":[{"name":"Department of Cardiology, RWTH Aachen University Hospital, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lehrke","sequence":"additional","affiliation":[{"name":"Department of Cardiology, RWTH Aachen University Hospital, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4048-6351","authenticated-orcid":false,"given":"Rafael","family":"Kramann","sequence":"additional","affiliation":[{"name":"Department of Nephrology, RWTH Aachen University Hospital, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9921-4284","authenticated-orcid":false,"given":"Peter","family":"Boor","sequence":"additional","affiliation":[{"name":"Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Lipp","sequence":"additional","affiliation":[{"name":"Pr\u00e4klinisches Zentrum f\u00fcr Molekulare Signalverarbeitung (PZMS), Institute of Cell Biology, Saarland University, Homburg\/Saar, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Laufs","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Hospital Leipzig, Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"M\u00e4rz","sequence":"additional","affiliation":[{"name":"Vth Department of Medicine, University Heidelberg, Mannheim Medical Faculty, Mannheim, Germany"},{"name":"Clinical Institute of Medical and Laboratory Diagnostics, Medical University Graz, Graz, Austria"},{"name":"Synlab Academy, Synlab Holding, Mannheim, 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