title: Inhibition of Activin Signaling Slows Progression of Polycystic Kidney Disease.
abstract: 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.
authors.affiliation: Departments of Human Genetics.
authors.forename: Wouter N
authors.initials: WN
authors.lastname: Leonhard
authors.affiliation: Departments of Human Genetics.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kunnen
authors.affiliation: Departments of Human Genetics.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Plugge
authors.affiliation: Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; and.
authors.forename: Arja
authors.initials: A
authors.lastname: Pasternack
authors.affiliation: Departments of Human Genetics.
authors.forename: Sebastian B T
authors.initials: SB
authors.lastname: Jianu
authors.affiliation: Pathology, and.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Veraar
authors.affiliation: Departments of Human Genetics.
authors.forename: Fatiha
authors.initials: F
authors.lastname: El Bouazzaoui
authors.affiliation: Department of Human Movement Sciences, Faculty of Behavior and Movement Sciences, Vrije Universiteit Amsterdam, MOVE Research Institute, Amsterdam, The Netherlands.
authors.forename: Willem M H
authors.initials: WM
authors.lastname: Hoogaars
authors.affiliation: Molecular Cell Biology and Cancer Genomics Centre Netherlands at the Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
authors.affiliation: Departments of Human Genetics.
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.affiliation: Pathology, and.
authors.forename: Emile
authors.initials: E
authors.lastname: De Heer
authors.affiliation: Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; and.
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
authors.affiliation: Departments of Human Genetics, d.j.m.peters@lumc.nl.
authors.forename: Dorien J M
authors.initials: DJ
authors.lastname: Peters
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors*; D000818:Animals; D018450:Disease Progression; D004847:Epithelial Cells; D005260:Female; D007668:Kidney / Q000166:cytology; D008297:Male; D051379:Mice; D007690:Polycystic Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction; D051899:Smad2 Protein / Q000502:physiology; D051900:Smad3 Protein / Q000502:physiology; D013997:Time Factors
chemical_list: D011993:Recombinant Fusion Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C000601041:sActRIIB-Fc fusion protein; D028341:Activins
keywords: ADPKD; Activin; TGF-beta; genetic renal disease; inhb; polycystic kidney disease