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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.

SUBMITTER: Sidhom EH

PROVIDER: S-EPMC7919729 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOxidative Stress, an imbalance in the pro-oxidant/antioxidant homeostasis, occurs in many physiological and non-physiological processes and several human diseases, including diabetes mellitus (DM) and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Since the incidence of G6PD deficiency in Jordan and many parts of the world is high, this study aimed to measure the effect of G6PD deficiency on the oxidative markers and the antioxidant glutathione (GSH) in diabetic and non-diabetic individuals.MethodsWhole blood G6PD deficiency was screened by the fluorescent spot method, and erythrocyte G6PD activity was determined using a quantitative assay. Since protein carbonyl (PC) and malondialdehyde (MDA) are the most widely measured markers for protein and lipid oxidation, respectively, plasma PC and MDA, in addition to blood GSH were determined by spectrophotometric assays, as biomarkers of oxidative stress.ResultsThe incidence of G6PD deficiency among the diabetic subjects was 15%. PC level in patients with diabetes and in G6PD-deficient subjects was 5.5 to 6-fold higher than in non-diabetic subjects with sufficient G6PD levels (p<0.001). This fold increase was doubled in diabetic patients with G6PD deficiency (p<0.001). Furthermore, the MDA level was significantly increased by 28-41% in G6PD-deficient, diabetics with sufficient G6PD, and diabetics with G6PD deficiency compared to MDA level in non-diabetic with sufficient G6PD. On the other hand, GSH was significantly reduced to half in G6PD-deficient subjects and in diabetics with G6PD-deficiency.ConclusionsThe results showed that diabetes and G6PD deficiency increased protein oxidation and lipid peroxidation. However, the combination of both disorders has an additive effect only on protein oxidation. On the other hand, GSH level is only reduced in G6PD deficiency. In addition, diabetes and G6PD deficiency appear to be genetically linked since the incidence of G6PD deficiency among people with diabetes is more than the general population.

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

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