Renal medullary HIF prolyl hydroxylases and salt sensitivity of blood pressure

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DESCRIPTION (provided by applicant): HIF prolyl hydroxylase domain-containing enzymes (PHDs) have been shown highly abundant in the renal medulla, which serve as oxygen sensors to regulate Hypoxia-inducible factor-la (HIF-1a) levels by promoting the degradation of this transcription factor. Given that the products of many HIF-1 a target genes such as nitric oxide synthase (NOS), cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) in the renal medulla are important antihypertensive factors and respond to high salt intake, we hypothesize that PHD regulation of HIF-1 a mediated gene activation importantly contributes to renal adaptation to high salt loading and thereby to the regulation of arterial blood pressure. To test this hypothesis, we will determine whether chronic renal adaptive response to high salt intake is associated with decrease in PHD activity and consequent activation of HIF-1 a-mediated gene transcription in the renal medulla of normal rats (Aim 1). We will further determine whether salt loading-induced alterations of PHD regulation of HIF-1 a are associated with tubular ion transport activity and where the salt-induced changes in PHD activity and expression occur along the nephron. We will also determine whether stimulation of PHD activity and overexpression of PHD2 gene to block HIF-1 a mediated gene expression in the renal medulla increases the salt sensitivity of arterial blood pressure (Aim 2). Finally, we will examine whether dysfunction in PHD regulation of HIF-1 a-mediated gene expression in the renal medulla contributes to salt-sensitive hypertension in Dahl salt-sensitive hypertensive rats and to explore the mechanisms responsible for the deficiency of PHD expression or activity in this rat strain with a focus on the possible role of local oxidative stress (Aim 3). The results from these proposed studies will define an important molecular mechanism mediating renal medullary adaptation to high salt intake and provide new insights into the pathogenesis of salt-sensitive hypertension. Relevance: High salt diet inactivates an enzyme containing prolyl hydroxylase domains (PHDs) in the kidney, which increases the expression of some protective genes and related factors, and thereby increases urinary salt excretion. If this enzyme is not working properly, excessively eaten salt cannot be removed, and salt-sensitive high blood pressure occurs. Clarification of this mechanism will ultimately suggest new therapies for treatment of high blood pressure.