Background: 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-CKD transition has not been fully elucidated.
Methods: TIMP2 expression was evaluated in multiple murine models, including unilateral ischemia-reperfusion injury (UIR), unilateral ureteral obstruction (UUO), and cisplatin-induced nephropathy. To investigate its function, we employed a tubule-specific, inducible TIMP2 knockout mouse model (Ksp-CreERT2; TIMP2fl/fl) and a tubular overexpression model.
Results: TIMP2 was significantly upregulated during the AKI-CKD transition across all tested models. Tubule-specific deletion of TIMP2 markedly attenuated renal fibrosis, suppressed senescence-associated 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-receptor LRP6, promoting its phosphorylation and subsequent β-catenin signaling activation, a process independent of its canonical matrix metalloproteinase (MMP) inhibitory function.
Conclusions: TIMP2 is a central mediator of maladaptive repair that links cell senescence and fibrotic reprogramming via the LRP6/β-catenin pathway. These findings suggest that TIMP2 serves not only as a biomarker but also as a potential therapeutic target for mitigating the AKI-CKD transition.
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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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