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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/F885    most recent 00519.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Traylor, A. Articles by Hill-Kapturczak, N. Search for Related Content PubMed PubMed Citation Articles by Traylor, A. Articles by Hill-Kapturczak, N.

Specificity protein 1 and Smad-dependent regulation of human heme oxygenase-1 gene by transforming growth factor-1 in renal epithelial cells

Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 26 December 2006 ; accepted in final form 9 June 2007

Excess transforming growth factor-1 (TGF-1) in the kidney leads to increased cell proliferation and deposition of extracellular matrix, resulting in progressive kidney fibrosis. TGF-1, however, stabilizes and attenuates tissue injury through the activation of cytoprotective proteins, including heme oxygenase-1 (HO-1). HO-1 catabolizes pro-oxidant heme into substances with anti-oxidant, anti-apoptotic, anti-fibrogenic, vasodilatory and immune modulatory properties. Little is known regarding the molecular regulation of human HO-1 induction by TGF-1 except that it is dependent on de novo RNA synthesis and requires a group of structurally related proteins called Smads. It is not known whether other DNA binding proteins are required to initiate transcription of HO-1 and, furthermore, the promoter region(s) involved in TGF-1-mediated induction of HO-1 has not been identified. The purpose of this study was to further delineate the molecular regulation of HO-1 by TGF-1 in human renal proximal tubular cells. Actinomycin D and nuclear run-on studies demonstrate that TGF-1 augments HO-1 expression by increased gene transcription and does not involve increased mRNA stability. Using transient transfection, mithramycin A, small interfering RNA, electrophoretic mobility shift assays, and decoy oligonucleotide experiments, a TGF-1-responsive region is identified between 9.1 and 9.4 kb of the human HO-1 promoter. This 280-bp TGF-1-responsive region contains a putative Smad binding element and specificity protein 1 binding sites, both of which are required for human HO-1 induction by TGF-1.

gene regulation; fibrosis; renal proximal tubule cell

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				J.-H. Kie, M. H. Kapturczak, A. Traylor, A. Agarwal, and N. Hill-Kapturczak Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1681 - 1691. [Abstract] [Full Text] [PDF]