Specificity protein 1 and Smad-dependent regulation of human heme oxygenase-1 gene by transforming growth factor-β1 in renal epithelial cells

Amie Traylor, Thomas Hock, Nathalie Hill-Kapturczak

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Excess transforming growth factor-β1 (TGF-β1) in the kidney leads to increased cell proliferation and deposition of extracellular matrix, resulting in progressive kidney fibrosis. TGF-β1, 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-β1 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-β1-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-β1 in human renal proximal tubular cells. Actinomycin D and nuclear run-on studies demonstrate that TGF-β1 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-β1-responsive region is identified between 9.1 and 9.4 kb of the human HO-1 promoter. This ∼280-bp TGF-β1-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-β1.

Original languageEnglish (US)
Pages (from-to)F885-F894
JournalAmerican Journal of Physiology - Renal Physiology
Volume293
Issue number3
DOIs
StatePublished - Sep 2007

Keywords

  • Fibrosis
  • Gene regulation
  • Renal proximal tubule cell

ASJC Scopus subject areas

  • Physiology
  • Urology

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