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

Nathalie Hill-Kapturczak, Leigh Truong, Vijayalakshmi Thamilselvan, Gary A. Visner, Harry S. Nick, Anupam Agarwal

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

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-β1 (TGF-β1) 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-β1 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-β1, we exposed confluent human renal proximal tubule cells to TGF-β1 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-β1 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-β1 resulted in marked induction of Smad7 mRNA with no effect on Smad6 expression. Overexpression of Smad7, but not Smad6, inhibited TGF-β1-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-β1 and manipulations of the Smad pathway to alter HO-1 expression may serve as a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)40904-40909
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number52
DOIs
StatePublished - Dec 29 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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