Format

Send to

Choose Destination
Cell Chem Biol. 2018 Feb 15;25(2):175-184.e4. doi: 10.1016/j.chembiol.2017.11.006. Epub 2017 Dec 14.

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

Author information

1
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
4
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
5
Department of Biomedicine, Molecular Nephrology, University of Basel, Basel 4031, Switzerland.
6
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: agreka@bwh.harvard.edu.

Abstract

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.

KEYWORDS:

BRAF; ER stress; ERK; MAPK; SB-682330; cell death; forskolin; glomerular disease; kidney disease; melanoma; post-mitotic cells

PMID:
29249695
PMCID:
PMC5819995
DOI:
10.1016/j.chembiol.2017.11.006
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center