Inhibition of Activin Signaling Slows Progression of Polycystic Kidney Disease.

Autor:	Leonhard WN; Departments of Human Genetics., Kunnen SJ; Departments of Human Genetics., Plugge AJ; Departments of Human Genetics., Pasternack A; Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; and., Jianu SB; Departments of Human Genetics., Veraar K; Pathology, and., El Bouazzaoui F; Departments of Human Genetics., Hoogaars WM; Department of Human Movement Sciences, Faculty of Behavior and Movement Sciences, Vrije Universiteit Amsterdam, MOVE Research Institute, Amsterdam, The Netherlands., Ten Dijke P; Molecular Cell Biology and Cancer Genomics Centre Netherlands at the Leiden University Medical Center, Leiden, The Netherlands., Breuning MH; Departments of Human Genetics., De Heer E; Pathology, and., Ritvos O; Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; and., Peters DJ; Departments of Human Genetics, d.j.m.peters@lumc.nl.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2016 Dec; Vol. 27 (12), pp. 3589-3599. Date of Electronic Publication: 2016 Mar 28.
DOI:	10.1681/ASN.2015030287
Abstrakt:	Autosomal dominant polycystic kidney disease (ADPKD), characterized by the formation of numerous kidney cysts, is caused by PKD1 or PKD2 mutations and affects 0.1% of the population. Although recent clinical studies indicate that reduction of cAMP levels slows progression of PKD, this finding has not led to an established safe and effective therapy for patients, indicating the need to find new therapeutic targets. The role of TGF-β in PKD is not clearly understood, but nuclear accumulation of phosphorylated SMAD2/3 in cyst-lining cells suggests the involvement of TGF-β signaling in this disease. In this study, we ablated the TGF-β type 1 receptor (also termed activin receptor-like kinase 5) in renal epithelial cells of PKD mice, which had little to no effect on the expression of SMAD2/3 target genes or the progression of PKD. Therefore, we investigated whether alternative TGF-β superfamily ligands account for SMAD2/3 activation in cystic epithelial cells. Activins are members of the TGF-β superfamily and drive SMAD2/3 phosphorylation via activin receptors, but activins have not been studied in the context of PKD. Mice with PKD had increased expression of activin ligands, even at early stages of disease. In addition, treatment with a soluble activin receptor IIB fusion (sActRIIB-Fc) protein, which acts as a soluble trap to sequester activin ligands, effectively inhibited cyst formation in three distinct mouse models of PKD. These data point to activin signaling as a key pathway in PKD and a promising target for therapy. (Copyright © 2016 by the American Society of Nephrology.)
Databáze:	MEDLINE
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