Downregulation of IGFBP7 and TIMP-2 protects kidney cells by regulating cell cycle in sepsis-associated acute kidney injury
Research Square (Research Square)(2023)
摘要
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.
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关键词
acute kidney injury,kidney cells,igfbp7,sepsis-associated
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