抄録
Transforming growth factor (TGF) -β constitutes a superf amily of multifunctional cytokines that regulate a variety of cellular responses including cell proliferation, apoptosis and extracellular matrix deposition. TGF-β1 is reportedly upregulated in tubulointerstitial fibrosis as characterized by epithelilal-mesenchymal transition (EMT) in the renal tubules and excessive accumulation of extracellular matrix with monocyte influx. Here we show that mice lacking Smad3, a key mediator of TGF-β signaling, are protected against tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO) . Primary culture of renal tubular epithelial cells from Smad3-null or wild-type mice demonstrated that TGF-β1-induced EMT of the renal tubules and autoinduction of TGF-β1 require Smad3 signaling. Cyclic stretching of cultured renal tubular epithelial cells that mimics distention of the renal tubules by UUO induces EMT and upregulation of TGF-βl in a Smad3-dependent manner. Exogenous bone marrow monocytes accelerate EMT of the cultured renal tubular epithelial cells and renal tubules in the obstructed kidney by UUO dependent on TGF-β1/Smad3 signaling. These data indicate that the Smad3 pathway is essential for the pathogenesis of renal tubulointerstitial fibrosis and suggests that small-molecule inhibitors of this pathway may have clinical application in the treatment of fibroinflammatory nephropathy.
