Zn2+ improves sepsis-induced acute kidney injury by up-regulating SIRT7-mediated Parkin acetylation

Objective: Zn²⁺ levels are reported to be correlated with kidney function.We explored the significance of Zn²⁺ in sepsis-induced acute kidney injury (SI-AKI) through the regulation of SIRT7 activity.

Methods: The sepsis rat model was established by cecal ligation and perforation (CLP), and intraperitoneally injected with ZnSO4 or SIRT7 Inhibitor 97491 (SIRT7i), with renal tubular injury assessed by H&E staining. In vitro, human renal tubular epithelial cells (HK-2) were induced with lipopolysaccharide to obtain a renal injury cell model, followed by ZnSO4 or SIRT7i and Autophagy Inhibitor (3-MA) treatment. Interleukin (IL)-1β, IL-18, Reactive Oxygen Species (ROS), Parkin acetylation level, kidney injury molecule 1 (KIM-1) and Neutrophil gelatinase-associated lipocalin (NGAL) expression levels were determined. The renal tubule injury, inflammation condition, and pyroptosis-related and autophagy-related protein levels were assessed. The Pyroptosis in kidney tissues and autophagosome formation were observed by transmission electron microscopy.

Results: Zn²⁺ alleviated renal injury in CLP rats, and inhibited Pyroptosis and its related protein levels by inhibiting SIRT7 activity in septic rat renal tissues. In vitro, Zn²⁺ increased HK-2 cell viability, and reduced KIM-1, NGAL, IL-1β, IL-18, NLRP3 inflammasome, Cleaved Caspase-1 and GSDMD-N levels and pyroptotic cell number. Zn²⁺ increased autophagosome number and LC3BII/LC3BI ratio, and decreased TOM20, TIM23, p62 and the mitochondrial ROS levels. Zn²⁺ increased Parkin acetylation by repressing SIRT7 activity. Inhibiting Mitophagy partially averted Zn²⁺-inhibited NLRP3 inflammasome activation and Apoptosis in HK-2 cells.

Conclusion: Zn²⁺ up-regulated Parkin acetylation by repressing SIRT7 activity to promote Mitophagy and inhibit NLRP3 inflammasome activation and Pyroptosis, thus improving SI-AKI.

Mitophagy; Pyroptosis; SIRT7 activity; Sepsis-induced acute kidney injury; Zn2+.