Kidney Week

Abstract: PO1988

GDC-0879 Rescues Lipid Peroxidation and Podocyte Dysfunction in Coenzyme Q-Deficient Kidney Disease

Session Information

• Podocyte Biology
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1204 Podocyte Biology

Authors

• Sidhom, Eriene-Heidi, Harvard Medical School, Boston, Massachusetts, United States

Eriene-Heidi Sidhom,

• Kim, Choah, Harvard Medical School, Boston, Massachusetts, United States

Choah Kim,

• Alimova, Maria, Broad Institute, Cambridge, Massachusetts, United States

Maria Alimova,

• Ting, May Theng, Columbia University Irving Medical Center, New York, New York, United States

May Theng Ting,

• Avila-Pacheco, Julian R., Broad Institute, Cambridge, Massachusetts, United States

Julian R. Avila-Pacheco,

• Watts, Andrew James baxter, Harvard Medical School, Boston, Massachusetts, United States

Andrew James baxter Watts,

• Vernon, Katherine Anne, Harvard Medical School, Boston, Massachusetts, United States

Katherine Anne Vernon,

• Marshall, Jamie L., Broad Institute, Cambridge, Massachusetts, United States

Jamie L. Marshall,

• Weins, Astrid, Brigham and Women's Hospital, Boston, Massachusetts, United States

Astrid Weins,

• Shaw, Jillian, Broad Institute, Cambridge, Massachusetts, United States

Jillian Shaw,

• Greka, Anna, Harvard Medical School, Boston, Massachusetts, United States

Anna Greka,

Background

Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of essential cells of the kidney filter called podocytes. Curiously, neighboring tubular epithelial cells are spared early in disease, despite their higher mitochondrial content. We therefore sought to illuminate new, cell-specific roles for CoQ, independent of its role in the electron transport chain (ETC).

Methods

Here we use CoQ deficiency caused by a monogenic disorder due to PDSS2 mutations as a model system with which to investigate the cell-specific mechanisms of disease. The resolution afforded by single nucleus RNA sequencing revealed podocyte-specific disease pathways in homozygous kd/kd (kidney disease) mice, the result of a spontaneous missense mutation in Pdss2 (V117M, Pdss2^kd/kd). We combine single nucleus transcriptomics with in vitro metabolomics and transcriptomics analyses to better understand the metabolic perturbations within this disease.

Results

Single nucleus RNA sequencing from kidneys of Pdss2^kd/kd mice, characterized by nephrotic syndrome and CoQ deficiency in all cells, identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound ameliorated kidney disease in Pdss2^kd/kd mice. In vitro, mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism leading to lipid peroxidation. Aberrant PUFA metabolism was confirmed in vivo, where the abundance of Gpx4, an enzyme that protects cells from lipid peroxidation, was elevated in disease and restored after treatment with GDC-0879. We demonstrate broader human disease relevance of these findings by uncovering patterns of Gpx4 and Braf/Mapk pathway gene expression in tissue from patients with several kidney diseases.

Conclusion

Our studies reveal ETC-independent roles for CoQ in podocyte injury and point to Braf/Mapk as a conserved, podocyte-specific pathway for the treatment of kidney diseases.

Funding

• NIDDK Support