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G protein\u2010coupled bile acid receptor 1 (TGR5) was previously shown to have beneficial effects on kidney diseases. The current study aimed to investigate whether TGR5 activation prevents kidney fibrosis and to clarify the underlying mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      TGR5 expression was examined in human fibrotic kidneys. Two animal models of renal fibrosis were used: unilateral ureteral obstruction (UUO) and unilateral ischemia\u2013reperfusion injury with contralateral nephrectomy (uIRIx) in wild\u2010type and\n                      <jats:italic>TGR5<\/jats:italic>\n                      knockout mice. Renal histology, extracellular matrix (ECM) deposition, and renal function were examined. In\u00a0vitro studies were performed on human proximal tubular HK2 cells by treating them with transforming growth factor\u2010\u03b21 and TGR5 agonists\/antagonists.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TGR5 was significantly downregulated in fibrotic human kidneys. In both UUO and uIRIx models, TGR5 activation by lithocholic acid alleviated renal fibrosis, reduced ECM deposition, and improved kidney function. Conversely,\n                      <jats:italic>Tgr5<\/jats:italic>\n                      knockout in mice exacerbated fibrotic injury. Mechanistically, TGR5 activation prevented fibrosis development, probably by enhancing NEDD4L\u2010mediated ubiquitination and degradation of phosphorylated Smad2\/3 by inhibiting the upstream PI3K\u2013SGK1 pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TGR5 activation protects against renal fibrosis by inhibiting the PI3K\u2013SGK1\u2013NEDD4L axis and promoting p\u2010Smad2\/3 degradation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70163","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:58:52Z","timestamp":1768463932000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Activation of\n                    <scp>TGR5<\/scp>\n                    Alleviates Renal Fibrosis by Promoting\n                    <scp>NEDD4L<\/scp>\n                    \u2010Mediated p\u2010Smad2\/3 Ubiquitination"],"prefix":"10.1111","volume":"242","author":[{"given":"Meng","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Hypertension, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Department of Physiology, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luosha","family":"Long","sequence":"additional","affiliation":[{"name":"Institute of Hypertension, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Department of Physiology, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoduo","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Zhongshan School of Medicine Sun Yat\u2010Sen University  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