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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

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 5

APOL1 G1–mediated cation transport reduces mitoATP production by impairing mitochondrial structure in T-REx-293 cells.

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APOL1 G1–mediated cation transport reduces mitoATP production by impairi...
(A) In T-REx-293 cells, induction of APOL1 G1 for 8, 12, or 24 hours increases the ADP/ATP ratio, which is normalized by VX-147 (n = 8). (B) Seahorse XFp real-time ATP rate assay shows that induction of APOL1 G1 for 8, 12, or 24 hours reduces mitoATP production, which is rescued by cotreatment with VX-147 (n = 5). Tet-induced glycoATP production is independent of APOL1 G1. (C) Targeted metabolomics measurement of TCA cycle metabolites in T-REx-293 G1 cells ± VX-147 for 8 hours (n = 3). (D) Schematic illustration of the assessment of mitochondrial respiratory conductance via the CK clamp in T-REx-293 G1 cells. Cells were treated for 12 hours with Tet ± VX-147. (E–M) Assessment of mitochondrial respiratory conductance via the creatine kinase clamp method in T-REx-293 G1 cells (n = 5). (E–G) Relationship between mitochondrial oxygen consumption (JO2) and ATP free energy (ΔGATP) in permeabilized cells energized with either 5 mM pyruvate/2.5 mM malate, or 5 mM αKG. G1 reduces JO2, which is rescued by VX-147, but not by supplemental pyruvate/malate or αKG. (K–M) Cotreatment with XSpC and JTV-519 in cells with G1 expression improved JO2. Changes in JO2 in the presence of pyruvate/malate (E) or αKG (H and K). Analysis of the linear relationship between energy demand (ATP:ADP, ΔGATP) and steady-state oxygen flux (JO2; F, I, and L) was used to determine respiratory conductance (JO2/ΔGATP), whereby a higher slope indicates greater respiratory kinetics in response to changes in energy demand (G, J, and M). All data are represented as mean ± SD. *P ≤ 0.05; **P ≤ 0.005; ***P ≤ 0.001; ****P ≤ 0.0001, ordinary 1-way ANOVA with Tukey’s multiple-comparison test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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