Zn2+ improves sepsis-induced acute kidney injury by upregulating SIRT7-mediated Parkin acetylation.

Abstract

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 sirtuin 7 (SIRT7) activity. 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 hematoxylin and eosin 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-methyladenine) 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. 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, gasdermin D-N levels, and pyroptotic cell number. Zn²⁺ increased autophagosome number and LC3BII/LC3BI ratio and decreased TOM20, TIM23, P62, and 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. Zn²⁺ upregulated Parkin acetylation by repressing SIRT7 activity to promote mitophagy and inhibit NLRP3 inflammasome activation and pyroptosis, thus improving SI-AKI.NEW & NOTEWORTHY Zn²⁺ upregulated Parkin acetylation by repressing sirtuin 7 activity to promote mitophagy and inhibit NLRP3 inflammasome activation and pyroptosis, thus improving sepsis-induced acute kidney injury.