Downregulation of IGFBP7 and TIMP-2 protects kidney cells by regulating cell cycle in sepsis-associated acute kidney injury

Author:

Wen Shiyao1,Wang Qian1,Jia Jia1,Gong Xiaoying1,Zhao Yang1,Li Guofu1

Affiliation:

1. Shengjing Hospital of China Medical University

Abstract

Abstract Background Tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) are biomarkers for early-stage diagnosis of acute kidney injury (AKI) and mediate the cell cycle transition from G1 to S. However, their pathophysiological roles in AKI remain obscure. Downregulation of IGFBP7 and TIMP-2 protects the kidney in AKI.Here, we aimed to elucidate the underlying mechanism and the contribution of the G1/S cell cycle arrest to AKI. Methods CLP and LPS were used to build the sepsis-associated AKI models in vivo and vitro respectively. The cyclinD, cyclinE, and pRB were detected to interpret the relationship between cell cyle arrest and sepsis-associated AKI. Then we studied the cell cycle, apoptosis, and autophagy after knocking-down the gene of IGFBP7 and TIMP-2. Finally, ribociclib was added to explore whether attenuation of LPS-induced apoptosis depend on G1/S cell cycle transition. Results Compared to sham mice, mice subjected to cecal ligation and puncture exhibited severe G1/S cell cycle arrest in the kidney and higher urine IGFBP7 and TIMP-2 levels. In vitro, IGFBP7 or TIMP-2 downregulation in lipopolysaccharide-treated HK-2 cells decreased inflammatory cytokine levels, reduced apoptosis and G1/S cell cycle arrest, and increased autophagy, relative to the control group. Furthermore, ribociclib was used to restore the G1/S cell cycle arrest, which was also attenuated by IGFBP7 or TIMP2 siRNA treatments. Conclusions Downregulation of IGFBP7 and TIMP-2 protects kidney cells from sepsis-induced acute kidney injury by regulating cell cycle, apoptosis and autophagy, and the protective effects are not totally reversed by alleviating cell cycle arrest.

Publisher

Research Square Platform LLC

Reference71 articles.

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