TIMP2 promotes AKI‐CKD transition by inducing tubular maladaptive repair and cell senescence via targeting Wnt/β‐catenin signalling

TL;DR

TIMP2 contributes to the progression from acute kidney injury to chronic kidney disease by causing harmful repair and cell aging through a specific signaling pathway.

Contribution

TIMP2 is identified as a key driver of maladaptive repair and fibrosis in the AKI-CKD transition via Wnt/β-catenin signaling.

Findings

TIMP2 deletion in tubular cells reduces fibrosis and improves mitochondrial function.

TIMP2 activates Wnt/β-catenin signaling through LRP6 in an MMP-independent manner.

TIMP2 overexpression worsens cellular senescence and fibrotic remodeling.

Abstract

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.

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.

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.

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.

TIMP2 is upregulated in injured renal tubules and promotes maladaptive repair and cell senescence.Genetic deletion of TIMP2 in tubular epithelial cells attenuates renal fibrosis and improves mitochondrial function.TIMP2 activates Wnt/β‐catenin signalling by binding to LRP6 via an MMP‐independent mechanism.

TIMP2 is upregulated in injured renal tubules and promotes maladaptive repair and cell senescence.

Genetic deletion of TIMP2 in tubular epithelial cells attenuates renal fibrosis and improves mitochondrial function.

TIMP2 activates Wnt/β‐catenin signalling by binding to LRP6 via an MMP‐independent mechanism.

1. TIMP2 is upregulated in injured renal tubules and promotes maladaptive repair and cell senescence.

2. Genetic deletion of TIMP2 in tubular epithelial cells attenuates renal fibrosis and improves mitochondrial function.

3. TIMP2 activates Wnt/β‐catenin signalling by binding to LRP6 via an MMP‐independent mechanism.

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