Inhibition of Activin Signaling Slows Progression of Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD), characterized by the formation of numerous kidney cysts, is caused byPKD1orPKD2mutations 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-βin PKD is not clearly understood, but nuclear accumulation of phosphorylated SMAD2/3 in cyst-lining cells suggests the involvement of TGF-βsignaling in this disease. In this study, we ablated the TGF-βtype 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 ofSMAD2/3target genes or the progression of PKD. Therefore, we investigated whether alternative TGF-βsuperfamily ligands account for SMAD2/3 activation in cystic epithelial cells. Activins are members of the TGF-βsuperfamily and drive SMAD2/3 phosphorylationviaactivin 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.