Induction of heme oxygenase-1 is an adaptive response to injury and plays an important cytoprotective role in acute renal failure due to ischemia-reperfusion, nephrotoxins, transplant rejection and rhabdomyolysis. Heme oxygenase catalyzes the rate-limiting step in heme degradation producing biliverdin, iron and carbon monoxide. Recent studies have demonstrated that the beneficial effects of this enzyme is a consequence of important antioxidant, anti-inflammatory and anti-apoptotic properties of the catalytic products. We, and others, have demonstrated that a number of factors (heme, nitric oxide, lipid and hydrogen peroxides, cytokines and growth factors), implicated in the pathogenesis of acute renal injury, are responsible for induction of heme oxygenase- 1. Our studies using human renal proximal tubular cells have recently discovered a novel enhancer region in the human heme oxygenase-1 gene that in conjunction with the promoter, specifically mediates gene regulation by heme and nitric oxide, but not by other known stimuli. The experiments outlined in this proposal will test the global hypothesis that specific trans-acting proteins interact with unique regulatory elements in the human heme oxygenase-l gene and mediate increased gene expression in response to heme and nitric oxide in human proximal tubular cells.
Aim I of this proposal will involve characterization of the enhancer and promoter regions by deletion analysis and electrophoretic mobility shift assays.
Aim II will evaluate DNA-protein interactions at the single nucleotide resolution by in vivo footprinting. The studies outlined in Aim III will evaluate the functional significance of potential DNA-protein binding regions in the enhancer element by-PCR-based site-directed mutagenesis.
Aim I V will involve studies to identify trans-acting proteins that bind to the enhancer element, using yeast one-hybrid screening. These studies will provide a basis for the development of specific molecular approaches to manipulate and fine tune heme oxygenase-l expression and thus exploit its cytoproteetive effects in renal pathophysiologic states.
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