Timp2, short for Tissue inhibitor of metalloproteinase-2, is a protein-coding gene. It has dual functions of inhibiting MMP (matrix metalloproteinase) activity and cytokine-like activity via receptor binding. It is involved in regulating extracellular matrix (ECM) structure and composition [5]. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, have been crucial in studying its functions.

In the context of traumatic brain injury (TBI), both TIMP2 and a TIMP2 mutant without MMP-inhibiting activity attenuated neurological deficits and BBB leakage in TBI mice, by inhibiting Src-dependent VE-cadherin internalization [1]. In sepsis-associated acute kidney injury (SA-AKI), kidney tubule-specific Timp2 knockout mice showed more severe kidney injury and elevated pyroptosis markers, while exogenous TIMP2 protected against kidney damage [2]. In renal fibrogenesis following ischemia-reperfusion injury, tubule-specific Timp2 knockout markedly attenuated renal fibrosis, and Timp2 was found to exacerbate Hedgehog (Hh) signaling, promoting mitochondrial fragmentation and metabolic reprogramming [3]. In sepsis-induced acute kidney injury, TIMP2-deficient mice had lower serum creatinine levels and decreased endoplasmic reticulum (ER) stress-mediated apoptosis compared to wild-type mice [4]. Also, downregulation of TIMP2 in stable, kidney-specific TIMP2 knockdown mice ameliorated cecal ligation and puncture (CLP)-induced proinflammatory cytokines, kidney dysfunction, and histopathological changes, through inhibition of the nuclear factor (NF)-κB pathway [6].

In conclusion, Timp2 plays diverse roles in multiple biological processes and disease conditions. Model-based research, especially using Timp2 KO/CKO mouse models, has revealed its significance in diseases like TBI, SA-AKI, and renal fibrogenesis. It is involved in processes such as maintaining blood-brain barrier integrity, regulating pyroptosis, mitochondrial function, and inflammation, providing potential therapeutic targets for these diseases.