GDC-0879, a BRAF 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 BRAF 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.
|Year of Publication||
Cell Chem Biol
2018 02 15
|PubMed Central ID||
R01 DK057683 / DK / NIDDK NIH HHS / United States
R01 DK103658 / DK / NIDDK NIH HHS / United States
R01 DK095045 / DK / NIDDK NIH HHS / United States
R01 DK099465 / DK / NIDDK NIH HHS / United States
R01 DK091218 / DK / NIDDK NIH HHS / United States
R01 DK062472 / DK / NIDDK NIH HHS / United States