{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T19:57:18Z","timestamp":1782935838918,"version":"3.54.5"},"reference-count":0,"publisher":"Ovid Technologies (Wolters Kluwer Health)","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Kidney360"],"abstract":"\n Background:<\/jats:title>\n Semaphorin 3C (SEMA3C) is a secreted protein that is essential for cardiovascular and renal development; however, its role in the development and progression of chronic kidney disease (CKD) remains unclear.<\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n We performed immunostaining for SEMA3C in human and murine kidneys. Subsequently, tamoxifen-inducible proximal tubule (PT)-specific\n Sema3c<\/jats:italic>\n functional knockout (FKO) mice (\n Ndrg1<\/jats:italic>\n CreERT2\/+<\/jats:sup>\n ;\n Sema3c<\/jats:italic>\n flox\/flox<\/jats:sup>\n , PT-\n Sema3c<\/jats:italic>\n FKO) were generated using the CRISPR\u2013Cas9 technique. To evaluate the renoprotective effects of PT-\n Sema3c<\/jats:italic>\n FKO, we employed two well-established models of CKD: the adenine-induced tubulointerstitial nephritis model and the high-fat diet (HFD)\/streptozotocin-induced diabetic nephropathy (DN) model.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n Immunostaining of human and murine kidneys showed high SEMA3C expression in the PTs, particularly in human tubulointerstitial nephropathy. In adenine-induced tubulointerstitial nephritis, control (\n Ctrl<\/jats:italic>\n ) littermates (\n Ndrg1<\/jats:italic>\n +\/+<\/jats:sup>\n ;\n Sema3c<\/jats:italic>\n flox\/flox<\/jats:sup>\n ) showed increased\n Sema3c<\/jats:italic>\n expression, whereas PT-\n Sema3c<\/jats:italic>\n FKO mice exhibited markedly reduced\n Sema3c<\/jats:italic>\n expression with attenuated fibrosis and inflammation. In contrast, in HFD\/streptozotocin-induced DN model, renal\n Sema3c<\/jats:italic>\n expression decreased in\n Ctrl<\/jats:italic>\n mice following DN induction, and neither proteinuria nor fibrosis was ameliorated in PT-\n Sema3c<\/jats:italic>\n FKO mice.\n In vitro<\/jats:italic>\n ,\n SEMA3C<\/jats:italic>\n expression in PT cells was upregulated by tumor necrosis factor-\u03b1 or transforming growth factor-\u03b2; however, it was downregulated under glucotoxic conditions. SEMA3C stimulation of kidney fibroblasts induced profibrotic marker expression and proliferation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n PT-derived SEMA3C promotes inflammation and fibrosis in adenine-induced tubulointerstitial nephritis.<\/jats:p>\n <\/jats:sec>","DOI":"10.34067\/kid.0000001242","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T18:14:18Z","timestamp":1782929658000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Proximal Tubule-Derived Semaphorin 3C Promotes Fibrosis in Adenine-Induced Tubulointerstitial Nephritis"],"prefix":"10.34067","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6409-4324","authenticated-orcid":false,"given":"Tomohiro","family":"Takehara","sequence":"first","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7859-1427","authenticated-orcid":false,"given":"Yoichiro","family":"Otaki","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunobu","family":"Ichikawa","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7317-9585","authenticated-orcid":false,"given":"Yuzuka","family":"Kuramasu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroe","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1958-239X","authenticated-orcid":false,"given":"Ryuhei","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Miyata","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Koizumi","sequence":"additional","affiliation":[{"name":"Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women\u2019s Medical University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayumi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7791-1916","authenticated-orcid":false,"given":"Keita","family":"Kamei","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0088-581X","authenticated-orcid":false,"given":"Haruki","family":"Ochi","sequence":"additional","affiliation":[{"name":"Graduate School of Science and Faculty of Science, Kobe University, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4565-3799","authenticated-orcid":false,"given":"Tetsu","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0339-9008","authenticated-orcid":false,"given":"Motoko","family":"Yanagita","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Kyoto University, Graduate school of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4617-9670","authenticated-orcid":false,"given":"Hiroaki","family":"Honda","sequence":"additional","affiliation":[{"name":"Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women\u2019s Medical University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9481-6673","authenticated-orcid":false,"given":"Ichiro","family":"Manabe","sequence":"additional","affiliation":[{"name":"Department of Disease Biology and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8672-7483","authenticated-orcid":false,"given":"Masafumi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,7,1]]},"container-title":["Kidney360"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.34067\/KID.0000001242","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T18:14:18Z","timestamp":1782929658000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.34067\/KID.0000001242"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":0,"URL":"https:\/\/doi.org\/10.34067\/kid.0000001242","relation":{},"ISSN":["2641-7650"],"issn-type":[{"value":"2641-7650","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]},"assertion":[{"value":"2026-01-02","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-12","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}