APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease

Two coding variants of apolipoprotein L1 (AP0Ł7), called C1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which C1 and C2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of AP0L1 protein, VX-147, to identify the upstream mechanism of C1-induced cytotoxicity. In HEK293 cells, we demonstrated that C1-mediated Na· import/K· efflux triggered activation of CPCR/IP3-mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX-147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that C1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from AP0L1G7 transgenic mice, we showed that IFN-y-mediated induction of C1 caused K· efflux, activation of CPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish AP0L1-mediated Na·/K· transport as the proximal driver of AP0L1mediated kidney disease.