Pirfenidone regulates obesity-related renal injury through the SIRT3 signaling pathway

Objective Pirfenidone (PFD) has been used to treat kidney fibrosis. However, the effects of PFD on obesity-related kidney injury and the underlying mechanisms are still poorly understood. Methods Male C57BL/6 J mice were fed a high-fat diet (HFD) for 20 weeks to induce kidney injury, and PFD was added to the feed of the mice in the PFD group beginning at 8 weeks. The controls were fed a normal control diet (NCD), and half of the mice were similarly treated with PFD. Indicators associated with lipid metabolism and kidney injury were assessed in vivo. Furthermore, human proximal tubular epithelial (HK−2) cells and human primary renal proximal tubule epithelial cells (PTECs) were incubated with palmitate (PA) and PFD, to investigate the effect of PFD on tubule cell injury in vitro. Single-cell sequencing analysis, molecular docking, and coimmunoprecipitation were subsequently used to explore the mechanisms of PFD action. Results PFD ameliorated metabolic abnormalities, inflammatory responses and oxidative stress induced by an HFD. PFD alleviated renal fatty acid oxidation and injury indicators in the HFD-fed mice and PA-treated renal tubular cells. PFD reversed the HFD/PA-induced decrease in SIRT3 protein expression. Moreover, transfection with si-SIRT3 abolished the beneficial effects of PFD on kidney injury and lipid metabolism in HK-2 cells. Conclusion In summary, our data revealed that PFD could mitigate obesity-related kidney injury in a SIRT3-dependent manner.