Datta, Somenath, Antonio, Brett M., Zahler, Nathan H., Theile, Jonathan W., Krafte, Doug, Zhang, Hengtao, Rosenberg, Paul B., Chaves, Alec B., Muoio, Deborah M., Zhang, Guofang, Silas, Daniel, Li, Guojie, Soldano, Karen, Nystrom, Sarah, Ferreira, Davis, Miller, Sara E., Bain, James R., Muehlbauer, Michael J., Ilkayeva, Olga, Becker, Thomas C., Hohmeier, Hans-Ewald, Newgard, Christopher B., and Olabisi, Opeyemi A.
Two coding variants of apolipoprotein L1 (APOL1), called G1 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 G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated [Na.sup.+] import/[K.sup.+] efflux triggered activation of GPCR/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 G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1G1 transgenic mice, we showed that IFN-[gamma]- mediated induction of G1 caused [K.sup.+] efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated [Na.sup.+]/[K.sup.+] transport as the proximal driver of APOL1-mediated kidney disease., Introduction Two African apolipoprotein L1 (APOL1) variants, named G1 (p.S342G and p.I384M) and G2 (deletion of p.N388/Y389), appear to have evolved to confer protection against the African sleeping sickness parasite [...]