{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:33:38Z","timestamp":1788784418817,"version":"build-2803163510"},"reference-count":52,"publisher":"American Society for Clinical Investigation","issue":"24","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["PJT-148628"],"award-info":[{"award-number":["PJT-148628"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100013528","name":"Diabetes Canada","doi-asserted-by":"crossref","award":["OG-3-23-5791-JK"],"award-info":[{"award-number":["OG-3-23-5791-JK"]}],"id":[{"id":"10.13039\/100013528","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Lundbeck Foundation","award":["R347-2020-2388"],"award-info":[{"award-number":["R347-2020-2388"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,22]]},"abstract":"<jats:p>We recently showed that cell surface translocation of the endoplasmic reticulum\u2013resident protein GRP78, when bound by activated \u03b1 2-macroglobulin (\u03b12M*), induces pro-fibrotic responses in glomerular mesangial cells in response to high glucose and regulates activation of the pro-fibrotic cytokine transforming growth factor-\u03b21 (TGF-\u03b21), implicating a pathogenic role in glomerulosclerosis. Interstitial fibrosis, largely mediated by proximal tubular epithelial cells (PTEC) and renal fibroblasts, develops later in kidney disease and correlates with functional decline. Here we investigated whether interstitial fibrosis was mediated by cell surface GRP78 (csGRP78)\/\u03b12M*. High glucose and TGF-\u03b21 increased csGRP78 and \u03b12M* in PTEC and renal fibroblasts, and their inhibition prevented fibrotic protein production. Interestingly, for TGF-\u03b21, this depended on inhibition of noncanonical signaling through YAP\/TAZ, with Smad3 activation unaffected. In vivo, type 1 diabetic Akita mice overexpressing TGF-\u03b21 were treated with either a neutralizing antibody for csGRP78 (C38) or \u03b12M* (F\u03b12M) or an inhibitory peptide blocking csGRP78\/\u03b12M* interaction, and mice with unilateral ureteral obstruction were treated with F\u03b12M or inhibitory peptide. Consistently, inhibition by antibody or peptide attenuated fibrosis and pro-fibrotic signaling. These findings show an important role for csGRP78\/\u03b12M* in mediating tubulointerstitial fibrosis in both diabetic and nondiabetic kidney disease and support their inhibition as a potential antifibrotic therapeutic intervention.<\/jats:p>","DOI":"10.1172\/jci.insight.183998","type":"journal-article","created":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T19:00:44Z","timestamp":1766343644000},"source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of cell surface GRP78 and activated \u03b12M interaction attenuates kidney fibrosis"],"prefix":"10.1172","volume":"10","author":[{"given":"Jackie","family":"Trink","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ifeanyi Kennedy","family":"Nmecha","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, McMaster University, 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