Downregulation of TIMP2 attenuates sepsis-induced AKI through the NF-kappa b pathway

作者：Li, Yi-Ming; Zhang, Jing; Su, Lian-Jiu; Kellum, John A.; Peng, Zhi-Yong^*

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2019, 1865(3): 558-569.

DOI：10.1016/j.bbadis.2018.10.041

• Tissue inhibitor of metalloproteinases 2
• Sepsis-induced acute kidney injury
• NF-kappa b pathway
• Apoptosis

Acute kidney injury (AKI) is a frequent complication of sepsis and contributes to increased morbidity and mortality. Urinary tissue inhibitor of metalloproteinases-2 (TIMP2) has been recently recognized as an early biomarker to predict AKI in critically ill patients. However, the biological functions of TIMP2 remain largely unknown. In this study, we investigated the role of TIMP2 in mediating inflammation and tubular cell apoptosis in AKI. In kidney tissue taken from mice exposed to cecal ligation and puncture (CLP) and in human kidney 2 (HK-2) cells exposed to lipopolysaccharide (LPS) in culture, TIMP2 expression was significantly upregulated. The expression of TIMP2 in the kidney tissue correlated with the severity of AKI in vivo. In cultured HK-2 cells, LPS challenge markedly induced cytokine release, and recombinant cytokines promoted TIMP2 expression and apoptosis. However, TIMP2 silencing ameliorated LPS-induced cytokine release, apoptosis, and cell injury. We further found that the effects of downregulation of TIMP2 on a suppression of release of inflammatory cytokines were mediated by p-P65. Stable, kidney-specific TIMP2 knockdown mice were transduced by injecting the TIMP2 knockdown lentiviral vector into kidney parenchyma. TIMP2 silencing ameliorated CLP-induced proinflammatory cytokines, kidney dysfunction as measured by serum creatinine level, and histopathological changes. Downregulation of TIMP2 showed renoprotective effects on endotoxin-induced AKI, which was associated with the anti-inflammatory activity through inhibition of the nuclear factor (NF)-kappa B pathway. Collectively, our results indicate that TIMP2 plays an important role in mediating sepsis-induced AKI through regulation of NF-kappa B. These findings reveal the pathogenic role of TIMP2 in AKI and suggest a novel target for the treatment of AKI.

• 出版日期2019-3-1
• 单位武汉大学