A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models.

Autor: Zhou Y; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Castonguay P; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Sidhom EH; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Clark AR; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Dvela-Levitt M; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Kim S; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Sieber J; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Wieder N; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Jung JY; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea., Andreeva S; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Reichardt J; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Dubois F; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Hoffmann SC; Medical Research Center, Medical Faculty Mannheim, University Heidelberg, Germany., Basgen JM; Life Sciences Institute, Charles R. Drew University of Science and Medicine, Los Angeles, CA 90059, USA., Montesinos MS; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Weins A; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA., Johnson AC; Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA., Lander ES; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Garrett MR; Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA., Hopkins CR; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA., Greka A; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2017 Dec 08; Vol. 358 (6368), pp. 1332-1336.
DOI: 10.1126/science.aal4178
Abstrakt: Progressive kidney diseases are often associated with scarring of the kidney's filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.
(Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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