It has been demonstrated that the activities of many paracrine or autocrine systems such as nitric oxide synthases, cyclooxyganses, heme oxygenases and others are much higher in the renal medulla than in the renal cortex. These local humoral systems have been indicated to importantly control the constancy of renal blood flow and oxygenation, sodium excretion and arterial blood pressure. However, the mechanism activating these renal medullary protective systems is still poorly understood. Our preliminary experiments have shown that a low PO2 milieu and corresponding activation of gene transcription in the renal medulla may contribute to the great activity of these paracrine and autocrine systems. An oxygen-sensitive transcription factor, hypoxia inducible factor-la (HIF-1alpha) was found highly expressed in the renal medulla and upregulated in response to decrease in tissue oxygenation or cell hypoxia. Inhibition of HIF-1alpha in this kidney region resulted in increase in arterial blood pressure and enhancement of the salt sensitivity of arterial blood pressure. Based on these data, we hypothesize that HIF-lalpha-activated transcription in the renal medulla may increase the expression of oxygen-sensitive genes, which contributes to the oxygen homeostasis and prevention of hypoxic injury in this kidney region and thereby participates in the control of renal function and arterial blood pressure. In this grant proposal, we will determine whether this HIF-1alpha-mediated gene transcription in the renal medulla is importantly involved in the renal adaptive response to high salt intake and whether blockade of HIF-1alpha increases the salt sensitivity of arterial blood pressure in rats. We will also determine whether alterations of HIF-1a levels influence the reactivity of renal medullary vessels to different vasoconstrictors and whether increased HIF-1alpha levels protect the renal medulla from vasoconstrictive or hypoxic injury. Furthermore, we will determine the functional significance of those HIF1alpha-activated genes in the control of renal function and arterial blood pressure by analyzing the expression of a prototype gene, heme oxygenase-1. Finally, we will determine whether an abnormality of HIF-1alpha-mediated gene transcription contributes to the increased salt sensitivity of arterial blood pressure in Dahl salt-sensitive hypertensive rats. These studies will clarify the underlying mechanism regulating renal medullary function and the salt sensitivity of arterial blood pressure and ultimately may suggest new therapies for the treatment of renal ischemia and hypertension at gene transcriptional level.
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