{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:17:40Z","timestamp":1791407860412,"version":"4.3.3"},"reference-count":53,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272208"],"award-info":[{"award-number":["82272208"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82241039"],"award-info":[{"award-number":["82241039"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82102273"],"award-info":[{"award-number":["82102273"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD), but the underlying mechanisms of this transition remain unclear. While TIMP2 is a known biomarker for AKI, its direct pathogenic role in the AKI\u2010CKD transition has not been fully elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>TIMP2 expression was evaluated in multiple murine models, including unilateral ischemia\u2010reperfusion injury (UIR), unilateral ureteral obstruction (UUO), and cisplatin\u2010induced nephropathy. To investigate its function, we employed a tubule\u2010specific, inducible TIMP2 knockout mouse model (Ksp\u2010CreERT2; TIMP2fl\/fl) and a tubular overexpression model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TIMP2 was significantly upregulated during the AKI\u2010CKD transition across all tested models. Tubule\u2010specific deletion of TIMP2 markedly attenuated renal fibrosis, suppressed senescence\u2010associated secretory phenotypes (SASP), and promoted tubular repair. Conversely, TIMP2 overexpression exacerbated cellular senescence and fibrotic remodeling. Mechanistically, TIMP2 was found to bind to the Wnt co\u2010receptor LRP6, promoting its phosphorylation and subsequent \u03b2\u2010catenin signaling activation, a process independent of its canonical matrix metalloproteinase (MMP) inhibitory function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>TIMP2 is a central mediator of maladaptive repair that links cell senescence and fibrotic reprogramming via the LRP6\/\u03b2\u2010catenin pathway. These findings suggest that TIMP2 serves not only as a biomarker but also as a potential therapeutic target for mitigating the AKI\u2010CKD transition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>TIMP2 is upregulated in injured renal tubules and promotes maladaptive repair and cell senescence.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Genetic deletion of TIMP2 in tubular epithelial cells attenuates renal fibrosis and improves mitochondrial function.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>TIMP2 activates Wnt\/\u03b2\u2010catenin signalling by binding to LRP6 via an MMP\u2010independent mechanism.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70605","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T04:27:44Z","timestamp":1769660864000},"source":"Crossref","is-referenced-by-count":3,"title":["TIMP2 promotes AKI\u2010CKD transition by inducing tubular maladaptive repair and cell senescence via targeting Wnt\/\u03b2\u2010catenin signalling"],"prefix":"10.1002","volume":"16","author":[{"given":"Dongxue","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine Zhongnan Hospital of Wuhan University  Wuhan China"},{"name":"Clinical Research Center of Hubei Critical Care Medicine  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haichuan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Critical Care 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