Renal Endothelial Dysfunction in Na-Sensitive Hypertensi

终末期肾病(ESRD)表现为高血压，高盐饮食加速了肾功能衰竭的进展。在人类患者和血管紧张素II盐敏感型高血压动物模型中，随着高血压的进展和终末期肾病的出现，可以观察到内皮功能障碍和肾脏血管阻力的增加。盐敏感型高血压的另一个共同特征是肾脏不能适当增加环氧二十碳三烯酸(EET)水平。此外，我们还提供了令人信服的证据，证明CYP450衍生的EETs具有抗高血压特性，并且是肾脏中的内皮衍生超极化因子(EDHF)。EETs还具有抗炎作用，可以保护肾脏血管免受高血压期间的损伤。细胞因子抑制肾脏EET的产生是解释与盐敏感性高血压相关的内皮功能障碍和肾小球损伤的一种机制。基于这些观察，我们假设，未能适当提高肾脏EET水平以应对高盐饮食会导致血管紧张素II高血压患者的内皮功能障碍、肾小球损伤和盐敏感性。我们将确定盐饮食、细胞因子和动脉血压对盐敏感型高血压患者EDHF调节、传入小动脉内皮功能和肾小球损伤的影响。拟议的研究将使用新开发的高选择性环氧化物水解酶抑制剂，提高EET水平，以确定它们在血管紧张素II盐敏感型高血压中降低动脉血压和改善肾脏微血管功能的能力。总的来说，建议的 这一应用中的实验将提供新的信息，即在血管紧张素II盐敏感型高血压期间，细胞因子和EET水平之间的相互作用在血压、肾脏微血管和肾小球功能的长期调节中的作用。

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.