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ADAM9 activates TGF\u03b21 by cleaving the latency\u2010associated peptide (LAP). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGF\u03b21.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed the expression of ADAM9 in the kidneys of mice and humans who were lupus prone. In vitro experiments were conducted using tubular epithelial cells (TECs) isolated from mice and explored the mechanisms responsible for the up\u2010regulation of ADAM9 and the subsequent activation of TGF\u03b21. To assess the role of ADAM9 in the development of tubular\u2010intestinal fibrosis in individuals with LN, we generated MRL\/<jats:italic>lpr<\/jats:italic> mice who were <jats:italic>Adam9<\/jats:italic> deficient.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ADAM9 was highly expressed in tubules from MRL<jats:italic>\/lpr<\/jats:italic> mice. The transcription factor hypoxia\u2010inducible factor\u20131\u03b1 was found to promote the transcription of ADAM9 in TECs. TECs from mice who were <jats:italic>Adam9<\/jats:italic> deficient and exposed to the hypoxia mimetic agent dimethyloxalylglycine failed to cleave the LAP to produce bioactive TGF\u03b21 from latent TGF\u03b21. Coculture of TECs from mice who were <jats:italic>Adam9<\/jats:italic> deficient with fibroblasts in the presence of dimethyloxalylglycine and latent TGF\u03b21 produced decreased amounts of type I collagen and \u03b1\u2013smooth muscle actin (SMA) by fibroblasts. MRL\/<jats:italic>lpr<\/jats:italic> mice who were <jats:italic>Adam9<\/jats:italic> deficient showed reduced interstitial fibrosis. At the translational level, ADAM9 expression in tissues and urine of patients with LN was found to increase.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Hypoxia promotes the expression of ADAM9 by TECs, which is responsible for the development of interstitial fibrosis in patients with LN by enhancing the TGF\u03b21 activation, which promotes fibroblasts to produce collagen and \u03b1\u2010SMA.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42987-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42987","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:44:27Z","timestamp":1726447467000},"page":"180-189","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Hypoxia Promotes the Expression of <scp>ADAM9<\/scp> by Tubular Epithelial Cells, Which Enhances Transforming Growth Factor \u03b21 Activation and Promotes Tissue Fibrosis in Patients With Lupus Nephritis"],"prefix":"10.1002","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6647-7130","authenticated-orcid":false,"given":"Masataka","family":"Umeda","sequence":"first","affiliation":[{"name":"Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, and Nagasaki University Graduate School of Biomedical Sciences  Nagasaki 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