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APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease
Somenath Datta, … , Christopher B. Newgard, Opeyemi A. Olabisi
Somenath Datta, … , Christopher B. Newgard, Opeyemi A. Olabisi
Published January 16, 2024
Citation Information: J Clin Invest. 2024;134(5):e172262. https://doi.org/10.1172/JCI172262.
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Research Article Nephrology Article has an altmetric score of 43

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

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Abstract

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+ import/K+ 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 APOL1 G1 transgenic mice, we showed that IFN-γ–mediated induction of G1 caused K+ 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+/K+ transport as the proximal driver of APOL1-mediated kidney disease.

Authors

Somenath Datta, Brett M. Antonio, Nathan H. Zahler, Jonathan W. Theile, Doug Krafte, Hengtao Zhang, Paul B. Rosenberg, Alec B. Chaves, Deborah M. Muoio, Guofang Zhang, Daniel Silas, Guojie Li, Karen Soldano, Sarah Nystrom, Davis Ferreira, Sara E. Miller, James R. Bain, Michael J. Muehlbauer, Olga Ilkayeva, Thomas C. Becker, Hans-Ewald Hohmeier, Christopher B. Newgard, Opeyemi A. Olabisi

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Figure 2

VX-147 does not reduce APOL1 localization to the PM.

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VX-147 does not reduce APOL1 localization to the PM.
(A) Representative ...
(A) Representative immunoblots of PM-localized, biotin-labeled APOL1 G1 and Na+/K+-ATPase proteins in T-REx-293 G1 cells after 8 hours of treatment, showing that VX-147 does not affect PM APOL1 G1 protein levels. APOL1 and vinculin levels in total cell lysate served as expression controls. Densitometric analysis data are represented in bar diagrams. Representative of 2 independent experiments. (B) Immunofluorescence staining showing PM and cytoplasmatic localization of APOL1 G1 (green) in T-REx-293 cells following 8 hours of treatment with Tet. Na+/K+-ATPase (red) serves as the PM reference protein. White arrow indicates area with cellular swelling. Scale bars: 11 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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