GDC-0879, a BRAFV600E Inhibitor, Protects Kidney Podocytes from Death

Progressive kidney diseases affect approximately 500 million people worldwide. Podocytes are terminally differentiated cells of the kidney filter, the loss of which leads to disease progression and kidney failure. To date, there are no therapies to promote podocyte survival. Drug repurposing may therefore help accelerate the development of cures in an area of tremendous unmet need. In a newly developed high-throughput screening assay of podocyte viability, we identified the BRAFV600E inhibitor GDC-0879 and the adenylate cyclase agonist forskolin as podocyte-survival-promoting compounds. GDC-0879 protects podocytes from injury through paradoxical activation of the MEK/ERK pathway. Forskolin promotes podocyte survival by attenuating protein biosynthesis. Importantly, GDC-0879 and forskolin are shown to promote podocyte survival against an array of cellular stressors. This work reveals new therapeutic targets for much needed podocyte-protective therapies and provides insights into the use of GDC-0879-like molecules for the treatment of progressive kidney diseases. [Display omitted] •HTS identifies the BRAFV600E inhibitor GDC-0879 as a podocyte-protective drug•GDC-0879 restores MAPK signaling in podocytes•GDC-0879 protects podocytes from an array of cell death inducers•The podocyte is the target of choice for the development of kidney therapeutics Sieber et al. implement a high-throughput screening assay of podocyte viability and find that the BRAF inhibitor GDC-0879 protects podocytes by restoring MAPK signaling, offering a novel repurposing strategy for targeted kidney therapeutics.