Abstract
Renal lipotoxicity was recently reported in several forms of kidney disease, including focal segmental glomerulosclerosis (FSGS). Susceptibility to FSGS in African Americans is associated with the presence of genetic variants of the Apolipoprotein L1 gene (APOL1) named G1 and G2. However, if and how endogenous APOL1 mediates cellular lipid homeostasis and mitochondrial function is unknown. Using transgenic mice expressing the APOL1 variants (G0, G1 or G2) under the endogenous promoter, we show that APOL1 risk variant expression in transgenic mice does not impair kidney function at baseline. However, APOL1 G1 expression worsens proteinuria and kidney function in mice characterized by experimental FSGS. APOL1 G1 expression in this FSGS-resembling model results in increased proteinuria, reduced kidney function, and lipid accumulation in kidney cortices. Increased triglyceride and cholesterol ester contents in kidney cortices correlated with loss of renal function. In vitro, we show that the expression of endogenous APOL1 G1/G2 in human urinary podocytes is associated with increased cellular triglyceride content and is accompanied by mitochondrial dysfunction in the presence of compensatory oxidative phosphorylation (OXPHOS) complexes elevation, when compared to G0/G0 podocytes. Our findings indicate that APOL1 risk variant expression increases the susceptibility to lipid-dependent podocyte injury, ultimately leading to mitochondrial dysfunction.