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Am J Physiol Renal Physiol 285: F515-F523, 2003. First published June 3, 2003; doi:10.1152/ajprenal.00137.2003
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An internal enhancer regulates heme- and cadmium-mediated induction of human heme oxygenase-1

Nathalie Hill-Kapturczak,1 Eric Sikorski,1 Christy Voakes,1 Jairo Garcia,1 Harry S. Nick,2 and Anupam Agarwal1

1Department of Medicine, Division of Nephrology, Hypertension, and Transplantation, and 2Department of Neuroscience, University of Florida, Gainesville, Florida 32610

Submitted 4 April 2003 ; accepted in final form 21 May 2003

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, releasing iron, carbon monoxide, and biliverdin. Induction of HO-1 is an adaptive and beneficial response in renal and nonrenal settings of tissue injury. The purpose of this study was to characterize the regulation of the human HO-1 gene in renal proximal tubule and aortic endothelial cells in response to heme and cadmium. Evaluation of multiple human HO-1 promoter-reporter constructs up to -9.1 kb demonstrated only a partial response to heme and cadmium. In an effort to mimic endogenous stimulus-dependent levels of HO-1 induction, we evaluated the entire 12.5 kb of the human HO-1 gene, including introns and exons, in conjunction with a -4.5-kb human HO-1 promoter and observed significant heme- and cadmium-mediated induction of the reporter gene, suggesting the presence of an internal enhancer. Enhancer function was orientation independent and required a region between -3.5 and -4.5 kb of the human HO-1 promoter. Our studies identified a novel enhancer internal to the human HO-1 gene that, in conjunction with the HO-1 promoter, recapitulates heme- and cadmium-mediated induction of the endogenous HO-1 gene. Elucidation of the molecular regulation of the human HO-1 gene will allow for the development of therapeutic strategies to manipulate HO-1 gene expression in pathological states.

gene transcription; renal proximal tubule cells; endothelial cells; heme proteins; molecular regulation


Address for reprint requests and other correspondence: A. Agarwal, Div. of Nephrology, Hypertension, and Transplantation, Box 100224 JHMHC, 1600 SW Archer Rd., Univ. of Florida, Gainesville, FL 32610 (E-mail: agarwal{at}nersp.nerdc.ufl.edu).




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