Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease
Eriene-Heidi Sidhom, … , Catarina M. Quinzii, Anna Greka
Eriene-Heidi Sidhom, … , Catarina M. Quinzii, Anna Greka
Published January 14, 2021
Citation Information: J Clin Invest. 2021;131(5):e141380. https://doi.org/10.1172/JCI141380.
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Research Article Cell biology Nephrology

Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease

Abstract

Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of Pdss2kd/kd mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in Pdss2kd/kd mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA-mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases.

Authors

Eriene-Heidi Sidhom, Choah Kim, Maria Kost-Alimova, May Theng Ting, Keith Keller, Julian Avila-Pacheco, Andrew J.B. Watts, Katherine A. Vernon, Jamie L. Marshall, Estefanía Reyes-Bricio, Matthew Racette, Nicolas Wieder, Giulio Kleiner, Elizabeth J. Grinkevich, Fei Chen, Astrid Weins, Clary B. Clish, Jillian L. Shaw, Catarina M. Quinzii, Anna Greka

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Figure 2

Histologic analysis of mouse kidney tissue demonstrates podocyte filter barrier rescue by GDC-0879.

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Histologic analysis of mouse kidney tissue demonstrates podocyte filter ...
(A) Electron micrographs of kidneys of control, vehicle-treated KDKD, and GDC-0879–treated KDKD mice to assess integrity of the kidney filter, measured by the appearance and number of podocyte foot processes (arrowheads). Diffuse foot process simplification (called effacement) is seen in glomeruli of vehicle-treated KDKD mice. Rescue of foot process effacement is observed following treatment with GDC-0879. Pod, podocyte; Mes, mesangial cell; CL, capillary lumen; FP, podocyte foot processes. Scale bars: 2 μm (upper); 1 μm (lower). (B) Vehicle-treated KDKD mice have significantly reduced podocyte foot process numbers, which is reversed following treatment with GDC-0879. n = 5 animals per condition; 14–16 images quantified per animal.Shapiro-Wilk normality test, 1-way ANOVA, Tukey’s multiple comparison test. (C) Decreased number of foot processes correlates with escalating individual animal proteinuria levels. **P < 0.01; ****P < 0.0001.