APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis

Abstract

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. If and how endogenous APOL1 may alter mitochondrial function by modifying cellular lipid metabolism is unknown. Using transgenic mice expressing the APOL1 variants (G0, G1 or G2) under 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 the podocyte inducible expression of nuclear factor of activated T-cells (NFAT), which we have found to cause FSGS. APOL1 G1 expression in this FSGS-model also results in increased triglyceride and cholesterol ester contents in kidney cortices, where lipid accumulation 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. Our findings indicate that APOL1 risk variant expression increases the susceptibility to lipid-dependent podocyte injury, ultimately leading to mitochondrial dysfunction.

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

“…Recently, incisive research has been published showing that Apoliprotein L1 gene ( APOL1) variants, G1 (S342G and I384M) and G2 (del388N389Y), are associated with mitochondrial dysfunction and cytotoxicity in podocytes, and contribute to lipotoxicity-induced renal injury in mice with focal segmental glomerulosclerosis ( 95 ). High-glucose–cultured podocytes have lower expression of APOL1 protein ( 96 ); however, the effect of the presence of APOL1 risk variants in podocytes in diabetic kidney has not yet been investigated.…”

Lessons From APOL1 Animal Models

“…Ge et al studied a triple transgenic model, BAC/APOL1 × podocin-rtTA × TRE/NFATc1nuc mouse model ( 26 ). These mice manifest elevated levels of triglycerides and cholesterol in kidney, as well as glomerulosclerosis.…”

Novel Human Podocyte Cell Model Carrying G2/G2 APOL1 High-Risk Genotype

“…Overexpression of APOL1-G1 and G2 variants has been proposed as a mechanism of APOL1-associated kidney diseases mainly affecting podocytes [18,24,26]. We performed various cell biological assays and assessed podocyte specific functions to validate our cell lines as a model to study mechanisms of APOL1-associated kidney disease.…”

“…Therefore, a better understanding of APOL1induced podocyte injury is still needed in order to derive effective therapies [18]. As such, cell and animal models overexpressing APOL1 G1 and G2 variants showed increased cytotoxicity leading to apoptosis, necrosis or inflammatory cell death (pyroptosis) [21][22][23][24], disrupted autophagic flux [18], altered mitochondrial function [25], increased lipid accumulation [26], increased potassium efflux and enhanced stress response pathways [27]. In most of these studies, a synthetic double-stranded RNA, polyinosinic-polycytidylic acid (poly(I:C)), which is an agonist of Toll-like receptor 3 (TLR3), was used for the activation of APOL1 driven by upregulation of interferon.…”