Hypoxia inducible factor (HIF)-1alpha is a transcriptional factor that is highly expressed in the renal medulla and regulates many anti-hypertensive genes, such as heme oxygenase-1, cyclooxygenase-2 and nitric oxide synthase-2, in this kidney region. Prolyl hydroxylase domain-containing protein-2 (PHD2) is the major enzyme to promote the degradation of HIF-1alpha in the renal medulla. In the last funding period, we proved that high salt intake reduced PHD2 mRNA levels in the renal medulla, which consequently induced HIF-1alpha-mediated activation of anti-hypertensive genes. This PHD2/HIF-1alpha-mediated molecular adaptation in the renal medulla is important for the kidneys to remove extra Na+ loading and maintain normal blood pressure under high salt intake. The question remains: how does high salt intake reduce PHD2 mRNA? Our preliminary studies showed that high salt diet enhanced the degradation of PHD2 mRNA in the renal medulla and that microRNA miR-429 was probably the upstream mediator for high salt-induced enhancement of PHD2 mRNA decay: 1) among the microRNAs that target PHD2 mRNA, miR-429 levels were increased by high salt intake in the renal medulla;2) miR-429 was shown to target PHD2 mRNA 3'-UTR;3) miR-429 reduced PHD2 mRNA levels in vitro and in vivo. Moreover, miR-429 inhibitor blocked the high salt- induced decrease in PHD2 mRNA in the renal medulla and produced salt sensitive hypertension in normal rats. We also detected impairment in miR-429 in the renal medulla in Dahl salt-sensitive hypertensive (SS) rats. Based on these preliminary data, we hypothesize that miR-429 regulation of PHD2/HIF-1alpha-mediated activation of anti-hypertensive genes in the renal medulla contributes to renal salt adaptation and participates in the controls of renal Na+ handling and blood pressure. To test this hypothesis, we will first determine whether chronic renal adaptation to high salt intake is associated with an increase in miR-429, which decreases PHD2 levels and activates HIF-1alpha-mediated transcriptions of anti-hypertensive genes in the renal medulla in normal rats. We will then determine whether inhibition of miR-429 function to prevent PHD2 reduction and to diminish HIF-1alpha-mediated activation of anti-hypertensive genes in the renal medulla will blunt pressure natriuresis and impair renal Na+ handling, leading to salt sensitive hypertension in normal rats. Finally, we will determine whether salt-sensitive hypertension in Dahl SS rats is associated with the dysfunction in miR-429- mediated molecular adaptation related to PHD2/HIF-1alpha-pathway in the renal medulla and also investigate the mechanisms that cause the deficiency of renal medullary miR-429 in this hypertensive model. The proposed studies will reveal a novel molecular mechanism mediating renal adaptation to high salt intake and provide new insights into the pathogenesis of salt-sensitive hypertension.

Public Health Relevance

High salt diet stimulates the expression of microRNA 429, which regulates the level of an enzyme called prolyl hydoxyase domain 2 (PHD2), leading to the activation of many anti-hypertensive genes in the kidney. These anti-hypertensive genes increase the production of factors that promote extra sodium excretion in the urine after high salt intake;if this microRNA-mediated pathway does not work properly, excessively eaten salt cannot be removed, and salt-sensitive high blood pressure occurs. Clarification of this mechanism may ultimately suggest new therapies for treatment of high blood pressure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZRG1)
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OH, Youngsuk
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Virginia Commonwealth University
Schools of Medicine
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