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Endoplasmic reticulum (ER) stress, a condition of disrupted ER homeostasis, is implicated in multiple pathophysiological processes, including kidney disease. Herein, we investigated the correlation between ER stress and septic AKI and further explored how TIMP2 regulated ER stress\u2010mediated apoptosis. To assess the role of TIMP2 in sepsis\u2010induced AKI, we used a cecal ligation and puncture (CLP) model in mice with tubule\u2010specific deficiency of TIMP2 (\n                    <jats:italic>Ksp<\/jats:italic>\n                    \u2010\n                    <jats:italic>Cre<\/jats:italic>\n                    \/\n                    <jats:italic>\n                      TIMP2\n                      <jats:sup>flox<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\/<\/jats:sup>\n                    <jats:italic>\n                      <jats:sup>flox<\/jats:sup>\n                    <\/jats:italic>\n                    ) and their wild\u2010type counterparts. Compared to the wild\u2010type mice, TIMP2\u2010deficient mice demonstrated lower serum creatinine levels and decreased ER stress\u2010mediated apoptosis when subjected to CLP. Interestingly, in human kidney (HK\u20102) cells, overexpression of TIMP2 caused ER stress, whereas TIMP2\u00a0knockdown attenuated lipopolysaccharide\u2010induced ER stress and apoptosis. TIMP2 interacted with the binding immunoglobulin protein, an ER chaperone, and facilitates its extracellular secretion, thereby triggering ER stress. This study identified that the deletion of TIMP2 in mouse tubules mitigated sepsis\u2010induced AKI by inhibiting ER stress\u2010mediated apoptosis, which might be a potential therapeutic strategy to alleviate renal injury.\n                  <\/jats:p>","DOI":"10.1096\/fj.202101555rr","type":"journal-article","created":{"date-parts":[[2022,2,26]],"date-time":"2022-02-26T14:19:22Z","timestamp":1645885162000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["TIMP2 mediates endoplasmic reticulum stress contributing to sepsis\u2010induced acute kidney injury"],"prefix":"10.1096","volume":"36","author":[{"given":"Nanhui","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxue","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianlong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianjiu","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3873-9607","authenticated-orcid":false,"given":"Zhiyong","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine Zhongnan Hospital of Wuhan University  Wuhan China"},{"name":"Department of Critical Care Medicine Center of Critical Nephrology University of Pittsburgh Medical Center  Pittsburgh Pennsylvania 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