Sirt6 deficiency exacerbates angiotensin II-induced lipid nephrotoxicity by affecting PLD6-derived cardiolipin metabolism in podocytes.

BACKGROUND AND AIMS: Perturbation of cardiolipin (CL) metabolism is associated with lipid nephrotoxicity. Recent findings provide new insights into the roles of CL-modulating proteins as critical determinants of podocyte function in chronic kidney disease (CKD). We previously demonstrated that Sirtuin 6 (Sirt6) is a compelling target inhibiting Angiotensin II (Ang II)-induced lipid dysregulation in podocytes. However, whether Sirt6 regulates podocyte CL metabolism is unknown. METHODS: Renal biopsy specimens of patients with hypertensive nephropathy (HN) were used in this study. Podocyte Sirt6-specific knockout mice were generated using the Cre-loxP system. The effect of Sirt6 on mitochondrial CL metabolism, especially the peroxidation and hydrolysis of CL, was investigated in Ang II-infusion mice and Ang II-induced cultured podocytes. RESULTS: Sirt6 and outer mitochondrial membrane protein phospholipase D family member 6 (PLD6) were decreased in the glomeruli of patients with HN. Ang II downregulated Sirt6 and PLD6 expression in podocytes in vitro and in vivo. Podocyte-specific deletion of Sirt6 exacerbated lipid droplets formation, CL accumulation and peroxidation, aggravated Ang II-induced mitochondrial dysfunction and cell apoptosis. Mechanically, Sirt6 maintained podocyte CL homeostasis, at least in part through PLD6 signaling-mediated CL metabolism. In addition, cardiolipin antioxidant Szeto-Schiller Peptide 31 (SS-31) treatment inhibited Ang II-induced lipid accumulation and CL peroxidation in podocytes. CONCLUSIONS: Our findings shed light on Sirt6's regulatory mechanisms on podocyte CL metabolism and suggest exploiting the Sirt6-PLD6 axis as a potential therapeutic target for protecting against lipid nephrotoxicity.