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.
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.
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