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 BRAFV600Einhibitor 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.

中文翻译：

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GDC-0879，BRAFV600E抑制剂，可保护肾脏足细胞免于死亡

进行性肾脏疾病影响全球约5亿人。足细胞是肾脏滤器的终末分化细胞，其丧失导致疾病进展和肾衰竭。迄今为止，还没有促进足细胞存活的疗法。因此，对药物的重新用途可能有助于在需求未得到满足的领域中加速治疗方法的开发。在一项新开发的足细胞生存力高通量筛选分析中，我们确定了BRAFV600E抑制剂GDC-0879和腺苷酸环化酶激动剂福司柯林是促进足细胞存活的化合物。GDC-0879通过反常激活MEK / ERK途径来保护足细胞免受伤害。佛司可林通过减弱蛋白质的生物合成来促进足细胞的存活。重要的，GDC-0879和佛司可林显示出针对一系列细胞应激物促进足细胞存活。这项工作揭示了急需的足细胞保护疗法的新治疗靶点，并为深入了解类GDC-0879分子用于治疗进行性肾脏疾病提供了见识。