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Although complement activation worsens IRI, the roles of upstream (C3) versus downstream (C5) components remain unclear. Renal IRI was surgically induced in C3 knockout (C3\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) and C5 knockout (C5\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) Lewis rats, and the renal function as well as histopathology were systematically assessed. Further, quantitative proteomics coupled with pathway enrichment analysis was performed to define complement\u2010dependent mechanisms. C3 and C5 deficiency conferred strong protection against renal IRI with improved renal function, reduced tubular necrosis, and lower expression of injury markers (KIM\u20101, NGAL). Post\u2010IRI, C3\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    enhanced mitochondrial, metabolic, and purine pathways while suppressing immune and extra\u2010cellular matrix programs. C5\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    affected extracellular matrix remodeling and structural pathways with modest immune suppression. We demonstrate for the first time that upstream C3\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    impacts a diverse range of renal injury and repair mechanisms compared to C5\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    alone, although both interventions successfully reduced IRI\u2010mediated injury. Together, these findings highlight strategies for future complement\u2010based therapies targeting the upstream or downstream cascade.\n                  <\/jats:p>","DOI":"10.14814\/phy2.71017","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T04:17:27Z","timestamp":1784607447000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effect of complement 3\/5 knockout on renal proteomics landscape after ischemia and reperfusion injury in rats"],"prefix":"10.14814","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9653-4044","authenticated-orcid":false,"given":"Dinesh","family":"Bhattarai","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Arkansas for Medical Science  Little Rock Arkansas USA"},{"name":"Division of Transplantation &amp; Advanced Hepatobiliary Surgery, Department of Surgery University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2860-7790","authenticated-orcid":false,"given":"Amod","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Arkansas for Medical Science  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5602-1982","authenticated-orcid":false,"given":"Madison","family":"McGraw","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Arkansas for Medical Science  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se\u2010Ran","family":"Jun","sequence":"additional","affiliation":[{"name":"Department of Medical Informatics University of Arkansas for Medical Sciences  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelam","family":"Joshi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Arkansas for Medical Science  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neriman","family":"Gokden","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Arkansas for Medical Sciences  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Mackintosh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Arkansas for Medical Sciences  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3994-5338","authenticated-orcid":false,"given":"Nirmala","family":"Parajuli","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Arkansas for Medical Science  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2017.05.012"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523\u20101755.2003.00737.x"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134\u2010024\u201007611\u20104"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.26.14672"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(20)30045\u20103"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1159\/000538241"},{"key":"e_1_2_12_8_1","unstructured":"Cell Death & Disease. 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