DGAT2 inhibition potentiates lipid droplet formation to reduce cytotoxicity in APOL1 kidney risk variants

Two APOL1 coding variants highly associated with African ancestry are major contributors to the large racial disparity in rates of human kidney disease. We previously demonstrated that recruitment of APOL1 risk variants G1 and G2 to lipid droplets (LDs) leads to reduced APOL1-mediated cytotoxicity in human podocytes. We now show in human kidney organoids that APOL1 is highly upregulated in response to interferon gamma (IFN-gamma), with greater increases in organoids of high risk (G1, G2) genotypes compared to wild-type (G0). We used CRISPR-Cas9 to develop APOL1G2/G2 kidney organoids from APOL1G0/G0 on an isogenic background. Bulk RNA sequencing of organoids revealed downregulation of genes involved in lipogenesis and lipid droplet biogenesis including SREBP1, SCD, ACSL3 and ACSL4, LMF1, LPL, SCD and FITM1 and upregulation of genes involved in fatty acid oxidation (e.g. CPT1) in APOL1G2/G2 kidney organoids. There were fewer LDs in unstimulated APOL1G2/G2 kidney organoids than in APOL1G0G0 organoids. Interestingly, whereas DGAT1 (diacylglycerol O-acyltransferase-1) inhibition reduced kidney organoid LD number, DGAT2 inhibition unexpectedly increased organoid LD number. DGAT2 inhibition promoted the recruitment of APOL1 to LDs with associated reduction of LC3, autophagic flux and cytotoxicity. These results show the importance of alterations in lipogenesis and LD formation as modulators of APOL1-associated cytotoxicity, and suggest inhibition of DGAT2 as a potential therapy to attenuate cytotoxic effects of APOL1 risk variants.