Professor Zhongnan Hospital of Wuhan University, United States
Introduction: Treatment of acute kidney injury (AKI) has proven to be a formidable challenge when primarily focusing on AKI itself, directing attention toward the long-term outcomes of AKI in survivors appears to be more promising. Tissue inhibitor of metalloproteinases 2 (TIMP2), a member of the tissue inhibitors of metalloproteinases family, is thought to be a cell cycle regulator capable of inducing cell cycle arrest in AKI. We hypothesized that TIMP2 would modulate the AKI-CKD transition.
Methods: We conducted single-cell transcriptome analysis and RNA-Seq analysis on various mouse models of AKI. In vivo experiments with tubular specific TIMP2 knockout mice and in vitro studies with primary renal tubular cells with TIMP2 deficiency were carried out to investigate the molecular mechanism of how TIMP2 participate and mediate cell cycle arrest and cell senescence.
Results: There are 3 main results from the current study. First, TIMP2 was ubiquitously expressed in kidney cells and tubular specific knock out TIMP2 reduced tubular epithelium cells (TECs) senescence and interstitial fibrosis in IR, UUO and aristolochic acid induced models of AKI-CKD. Second, clearance of senescent tubular cells by senolytics attenuated kidney fibrosis, rejuvenated tubular proliferation. Third, in vitro studies confirmed that absence of TIMP2 reduced cell senescence, dedifferentiation and alleviated tubular cell dedifferentiation. Overexpression of TIMP2 exacerbated tubular senescence, evidenced by increased detection of p21 expression and senescence-associated β-galactosidase activity. Besides, treatment of a cultured fibroblast cell line (NRK-49F) with recombinant timp2 induced fibroblast activation.
Conclusions: Our results suggest that TIMP2 promotes tubular maladaptive repair and renal fibrosis through the induction of tubular senescence and crosstalk between tubular cells and interstitial fibroblasts.
