Smad7-dependent regulation of heme oxygenase-1 by transforming growth factor-beta in human renal epithelial cells

Heme oxygenase-l (HO-1), a 32-kDa microsomal enzyme, is induced as a benefi cial and adaptive response in cells/tissues exposed to oxidative stress. Tr ansforming growth factor-beta1 (TGF-beta1) is a regulatory cytokine that ha s been implicated in a variety of renal diseases where it promotes extracel lular matrix deposition and proinflammatory events. We hypothesize that the release of TGF-beta1 via autocrine and/or paracrine pathways may induce HO -1 and serve as a protective response lin renal injury. To understand the m olecular mechanism of HO-1 induction by TGF-beta1, we exposed confluent hum an renal proximal tubule cells to TGF-beta1 and observed a significant indu ction of HO-1 mRNA at 4 h with a maximal induction at 8 h. This induction w as accompanied by increased expression of HO-1 protein. TGF-beta1 treatment in conjunction with actinomycin D or cycloheximide demonstrated that induc tion of HO-1 mRNA requires de novo transcription and, in part, protein synt hesis. Exposure to TGF-beta1 resulted in marked induction of Smad7 mRNA wit h no effect on Smad6 expression. Overexpression of Smad7, but not Smad6, in hibited TGF-beta1-mediated induction of endogenous HO-1 gene expression. We speculate that the induction of HO-1 in the kidney is an adaptive response to the inflammatory effects of TGF-beta1 and manipulations of the Smad pat hway to alter HO-1 expression may serve as a potential therapeutic target.