Timp2, or Tissue inhibitor of metalloproteinase-2, is a molecule with dual functions. It can inhibit MMP activity and display cytokine-like activity via receptor binding. It plays a role in regulating extracellular matrix (ECM) structure and composition as MMPs are major mediators of ECM turnover [5]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In various disease models, Timp2 shows diverse effects. In traumatic brain injury mouse models, both TIMP2 and a mutant without MMP-inhibiting activity attenuated neurological deficits and BBB leakage, through an MMP-independent mechanism involving α3β1 integrin, Src activation, and VE-cadherin internalization [1]. In sepsis-associated acute kidney injury, kidney tubule-specific Timp2 knockout mice had more severe kidney injury and elevated pyroptosis markers, while exogenous TIMP2 protected against kidney damage, suggesting TIMP2 can attenuate tubular pyroptosis [2]. In renal fibrogenesis following ischemia-reperfusion injury, tubule-specific Timp2 knockout markedly attenuated renal fibrosis, and RNA-sequencing showed Timp2 was associated with mitochondrial dynamics and glycolysis [3]. In sepsis-induced acute kidney injury, TIMP2-deficient mice had lower serum creatinine levels and decreased ER stress-mediated apoptosis, and in HK-2 cells, TIMP2 overexpression caused ER stress while knockdown alleviated it [4]. Also, downregulation of TIMP2 in mice transduced with a knockdown lentiviral vector ameliorated CLP-induced proinflammatory cytokines and kidney dysfunction, indicating TIMP2 mediates sepsis-induced AKI through the NF-κB pathway [6].

In conclusion, Timp2 is involved in multiple biological processes and disease conditions. Model-based research, especially using Timp2 KO/CKO mouse models, has revealed its role in diseases like traumatic brain injury, sepsis-associated acute kidney injury, and renal fibrogenesis. These findings contribute to understanding the mechanisms of these diseases and may offer potential therapeutic targets related to Timp2.

References:

1. Tang, Jingshu, Kang, Yuying, Zhou, Yujun, Wu, Lei, Peng, Ying. 2023. TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization. In The Journal of clinical investigation, 134, . doi:10.1172/JCI164199. https://pubmed.ncbi.nlm.nih.gov/38015626/

2. Xu, Dongxue, Jiang, Jun, Liu, Ye, Li, Yiming, Peng, Zhiyong. 2024. TIMP2 protects against sepsis-associated acute kidney injury by cAMP/NLRP3 axis-mediated pyroptosis. In American journal of physiology. Cell physiology, 326, C1353-C1366. doi:10.1152/ajpcell.00577.2023. https://pubmed.ncbi.nlm.nih.gov/38497110/

3. Pang, Jingjing, Xu, Dongxue, Zhang, Xiaoyu, Li, Yiming, Peng, Zhiyong. 2025. TIMP2-mediated mitochondrial fragmentation and glycolytic reprogramming drive renal fibrogenesis following ischemia-reperfusion injury. In Free radical biology & medicine, 232, 244-259. doi:10.1016/j.freeradbiomed.2025.02.020. https://pubmed.ncbi.nlm.nih.gov/39986488/

4. Jiang, Nanhui, Huang, Rong, Zhang, Jiahao, Su, Lianjiu, Peng, Zhiyong. . TIMP2 mediates endoplasmic reticulum stress contributing to sepsis-induced acute kidney injury. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 36, e22228. doi:10.1096/fj.202101555RR. https://pubmed.ncbi.nlm.nih.gov/35218571/

5. Peeney, David, Liu, Yueqin, Lazaroff, Carolyn, Gurung, Sadeechya, Stetler-Stevenson, William G. . Unravelling the distinct biological functions and potential therapeutic applications of TIMP2 in cancer. In Carcinogenesis, 43, 405-418. doi:10.1093/carcin/bgac037. https://pubmed.ncbi.nlm.nih.gov/35436325/

6. Li, Yi-Ming, Zhang, Jing, Su, Lian-Jiu, Kellum, John A, Peng, Zhi-Yong. 2018. Downregulation of TIMP2 attenuates sepsis-induced AKI through the NF-κb pathway. In Biochimica et biophysica acta. Molecular basis of disease, 1865, 558-569. doi:10.1016/j.bbadis.2018.10.041. https://pubmed.ncbi.nlm.nih.gov/30562560/