End stage renal disease (ESRD) is manifest in hypertension and the progression of renal failure is accelerated by a high salt diet. In human patients and angiotensin II salt-sensitive hypertensive animal models, endothelial dysfunction and increased renal vascular resistance are observed as hypertension progresses and ESRD becomes evident. Another common feature of salt-sensitive hypertension is the inability of the kidney to properly increase epoxyeicosatrienoic acid (EET) levels. Others and we have provided compelling evidence that CYP450-derived EETs have anti-hypertensive properties and are endothelial-derived hyperpolarizing factors (EDHF) in the kidney. EETs also possess anti-inflammatory actions that could protect the kidney vasculature from injury during hypertension. Cytokine suppression of kidney EET production is a mechanism that could explain endothelial dysfunction and glomerular injury associated with salt-sensitive hypertension. Based on these observations, we hypothesis that a failure to properly increase kidney EET levels in response to high dietary salt contributes to endothelial dysfunction, glomerular injury, and salt-sensitivity in angiotensin II hypertension. We will determine the effects of salt diet, cytokines and arterial blood pressure on EDHF regulation, afferent arteriolar endothelial function and glomerular injury in salt-sensitive hypertension. The proposed studies will employ newly developed highly selective epoxide hydrolase inhibitors that increase EET levels to determine their ability to lower arterial blood pressure and improve renal microvascular function in angiotensin II salt-sensitive hypertension. Collectively, the proposed experiments in this application will provide novel information on the interaction between cytokines and EET levels in the long-term regulation of blood pressure and renal microvascular and glomerular function during angiotensin II salt-sensitive hypertension.

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National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Georgia Regents University
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