Inhibition of Activin signaling slows progression of Polycystic Kidney Disease in mice.

摘要: 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, they have not yet led to an established safe and effective therapy for patients, indicating the need to find new therapeutic targets. The role of transforming growth factor β (TGFβ) in PKD is not clearly understood but nuclear accumulation of pSMAD2/3 in cyst-lining cells suggests the involvement of TGFβ signaling in PKD. In this study we ablated the TGFβ type I receptor (also termed activing receptor-like kinase 5 (ALK5)) in renal epithelial cells of PKD mice, which had little to no effect on the expression of SMAD2/3 target genes, or on the progression of PKD. These data suggest that alternative TGFβ superfamily ligands may account for SMAD2/3 activation in cystic epithelial cells. Activins are members of the TGFβ superfamily and drive SMAD2/3 phosphorylation via Activin receptors and have not yet been studied before in the context of PKD. Already in mice with early PKD, we found increased expression of Activin ligands. In addition, treatment with a soluble Activin receptor IIB fusion protein (sActRIIB-Fc), 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 player in PKD, and as a promising target for therapy.