Transforming growth factor-β inhibits cystogenesis in human autosomal dominant polycystic kidney epithelial cells
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure and characterized by the formation of multiple fluid-filled cysts in the kidneys. It is believed that environmental factors may play an important role in the disease progression. However, the molecular identity of autocrine/paracrine factors influencing cyst formation is largely unknown. In this study, we identified transforming growth factor-Î²2 (TGF-Î²2) secreted by normal human kidney (NHK) and ADPKD cells as an inhibitor of cystogenesis in 3D culture system using ADPKD cells from human kidneys. TGF-Î²2 was identified in conditioned media (CM) of NHK and ADPKD cells as a latent factor activated by heat in vitro. While all TGF-Î² isoforms recombinant proteins (TGF-Î²1, -Î²2, or -Î²3) displayed a similar inhibitory effect on cyst formation, TGF-Î²2 was the predominant isoform detected in CM. The involvement of TGF-Î²2 in the suppression of cyst formation was demonstrated by using a TGF-Î²2 specific blocking antibody and a TGF-Î² receptor I kinase inhibitor. TGF-Î²2 inhibited cyst formation by a mechanism other than activation of p38 mitogen-activated protein (MAP) kinase that mediated cell death in ADPKD cells. Further, we found that TGF-Î²2 modulated expression of various genes involved in cell–cell and cell–matrix interactions and extracellular matrix proteins that may play a role in the regulation of cystogenesis. Collectively, our results suggest that TGF-Î²2 secreted by renal epithelial cells may be an inhibitor of cystogenesis influencing the progression of ADPKD. âº We identified inhibitory factor of cystogenesis secreted by kidney epithelial cells. âº TGFÎ² is secreted as a latent inhibitory factor of cystogenesis. âº TGFÎ²2 is the major endogenous TGFÎ² isoform secreted by renal epithelial cells. âº TGFÎ² activity possibly limits cystogenesis in ADPKD.