ABSTRACT
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-ß2 (TGF-ß2) 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-ß2 was identified in conditioned media (CM) of NHK and ADPKD cells as a latent factor activated by heat in vitro. While all TGF-ß isoforms recombinant proteins (TGF-ß1, -ß2, or -ß3) displayed a similar inhibitory effect on cyst formation, TGF-ß2 was the predominant isoform detected in CM. The involvement of TGF-ß2 in the suppression of cyst formation was demonstrated by using a TGF-ß2 specific blocking antibody and a TGF-ß receptor I kinase inhibitor. TGF-ß2 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-ß2 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-ß2 secreted by renal epithelial cells may be an inhibitor of cystogenesis influencing the progression of ADPKD.
