Abstract
Heme oxygenase-1 (HO-1), a 32-kDa microsomal enzyme, is induced as a beneficial and adaptive response in cells/tissues exposed to oxidative stress. Transforming growth factor-beta1 (TGF-beta1) is a regulatory cytokine that has been implicated in a variety of renal diseases where it promotes extracellular 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 in renal injury. To understand the molecular mechanism of HO-1 induction by TGF-beta1, we exposed confluent human renal proximal tubule cells to TGF-beta1 and observed a significant induction of HO-1 mRNA at 4 h with a maximal induction at 8 h. This induction was accompanied by increased expression of HO-1 protein. TGF-beta1 treatment in conjunction with actinomycin D or cycloheximide demonstrated that induction of HO-1 mRNA requires de novo transcription and, in part, protein synthesis. Exposure to TGF-beta1 resulted in marked induction of Smad7 mRNA with no effect on Smad6 expression. Overexpression of Smad7, but not Smad6, inhibited 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 pathway to alter HO-1 expression may serve as a potential therapeutic target.
Highlights
Kidney diseases such as IgA nephropathy, focal and segmental glomerulosclerosis, crescentic glomerulonephritis, lupus nephritis, diabetic nephropathy, and chronic rejection are characterized by the deposition of extracellular matrix and have increased expression of transforming growth factor-1 (TGF1)1 in glomeruli and tubulointerstitium as compared with
We hypothesized that the induction of cytoprotective enzymes such as Heme oxygenase-1 (HO-1) may explain the paradoxical effects of Transforming growth factor-1 (TGF-1) in response to renal injury
HPTCs treated with TGF-1 at concentrations of 0.05, 0.5, and 2.0 ng/ml exhibited a significant, dose-dependent induction in HO-1 mRNA of 6, 12, and 13-fold, respectively, over control (PBS) at 4 h (Fig. 1A)
Summary
Kidney diseases such as IgA nephropathy, focal and segmental glomerulosclerosis, crescentic glomerulonephritis, lupus nephritis, diabetic nephropathy, and chronic rejection are characterized by the deposition of extracellular matrix and have increased expression of transforming growth factor-1 (TGF1) in glomeruli and tubulointerstitium as compared with. The initial purpose of this study was to evaluate the molecular mechanism of TGF-1-mediated induction of the human HO-1 gene in renal epithelial cells as well as to elucidate the signaling pathways involved in HO-1 gene induction. TGF- initiates signaling through type I (TR-I) and type II (TR-II) receptors, binding directly with TR-II, which interacts transiently with TR-I, forming a heteromeric complex [11]. The molecular mechanism of TGF- signal transduction from the cell surface to the nucleus has been recently identified to occur through a novel group of structurally related proteins called Smads [12, 13]. Receptor-regulated Smad proteins oligomerize with the common mediator Smad, which includes Smad in vertebrates [17]. Smad is a specific inhibitor of BMP signaling [22], whereas Smad inhibits BMP and TGF-1 signaling [23,24,25]
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