DGAT2 Inhibition Potentiates Lipid Droplet Formation To Reduce Cytotoxicity in APOL1 Kidney Risk Variants

Area of Science:

• Nephrology
• Genetics
• Cell Biology

Background:

• Two apolipoprotein L1 (APOL1) gene variants are strongly linked to African ancestry and are primary drivers of kidney disease racial disparities.
• Previous research showed that sequestering APOL1 risk variants G1 and G2 into lipid droplets reduces their toxicity in human podocytes.

Purpose of the Study:

• To investigate the role of lipogenesis and lipid droplet formation in APOL1-associated kidney disease.
• To explore the therapeutic potential of targeting diacylglycerol O-acyltransferases (DGATs) in APOL1 nephropathy.

Main Methods:

• CRISPR-Cas9 gene editing was used to create human-derived APOL1 risk variant (G2/G2) and wild-type (G0/G0) kidney organoids.
• Organoids were treated with IFN-γ and inhibitors of DGAT1 and DGAT2 to examine effects on APOL1 expression, lipid droplet dynamics, and cytotoxicity.
• Bulk RNA sequencing was performed to analyze gene expression changes in response to treatments.

Main Results:

• APOL1 was significantly upregulated by IFN-γ in kidney organoids, with higher induction in high-risk G1 and G2 genotypes.
• High-risk APOL1^G2/G2 organoids showed altered gene expression related to lipogenesis and fatty acid oxidation, with fewer lipid droplets compared to G0/G0 organoids.
• DGAT1 inhibition decreased lipid droplet numbers, while DGAT2 inhibition unexpectedly increased them, promoting APOL1 recruitment to lipid droplets and reducing cytotoxicity.

Conclusions:

• Lipogenesis and lipid droplet formation are key regulators of APOL1-mediated cytotoxicity.
• Inhibiting DGAT2 presents a promising therapeutic avenue for mitigating the harmful effects of APOL1 risk variants in kidney disease.