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A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models.
Zhou, Yiming; Castonguay, Philip; Sidhom, Eriene-Heidi; Clark, Abbe R; Dvela-Levitt, Moran; Kim, Sookyung; Sieber, Jonas; Wieder, Nicolas; Jung, Ji Yong; Andreeva, Svetlana; Reichardt, Jana; Dubois, Frank; Hoffmann, Sigrid C; Basgen, John M; Montesinos, Mónica S; Weins, Astrid; Johnson, Ashley C; Lander, Eric S; Garrett, Michael R; Hopkins, Corey R; Greka, Anna.
Afiliação
  • Zhou Y; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Castonguay P; 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.
  • Clark AR; 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.
  • Kim S; 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.
  • Wieder N; 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.
  • Andreeva S; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Reichardt J; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Dubois F; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Hoffmann SC; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Basgen JM; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Montesinos MS; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Weins A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Johnson AC; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Lander ES; Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea.
  • Garrett MR; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Hopkins CR; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Greka A; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Science ; 358(6368): 1332-1336, 2017 12 08.
Article em En | MEDLINE | ID: mdl-29217578
ABSTRACT
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteinúria / Glomerulosclerose Segmentar e Focal / Canais de Cátion TRPC / Hipertensão Renal / Indazóis Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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XML
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteinúria / Glomerulosclerose Segmentar e Focal / Canais de Cátion TRPC / Hipertensão Renal / Indazóis Idioma: En Ano de publicação: 2017 Tipo de documento: Article