MICROPUNCTURE STUDY OF KIDNEY FUNCTION

描述：(改编自申请者摘要)远景目标 这项建议是为了更好地了解肾脏的调节机制。 激素旁分泌和类胡萝卜素对血流动力学和肾小球功能的影响 健康和疾病方面的代理人。该提案继续侧重于机制。 肾脏中血管反应性和受体信号通路的研究 遗传性高血压发生发展过程中的微循环。独一无二的 重叠主题的协调研究的组合旨在获得 对肾脏过度的调控机制的洞察 血管收缩和肾小管-肾小球反馈活动增加 自发性高血压大鼠(SHR)。这项建议是在先前建议的基础上提出的 首席调查员的活体观察，表明 自发性高血压大鼠肾血管对血管紧张素II的反应性 由于血管扩张剂提供的缓冲有缺陷，引发了 CAMP途径。自发性高血压病的主要cAMP异常表现为 定位于受体-Gs-蛋白偶联。强化的肾脏 对加压素(AVP)的血管收缩反应在SHR中也可见，似乎是 这是由于V1AVP受体的活性增加。这项提议将 继续评估夸大肾脏的中心假说 血管收缩是由血管收缩药剂的直接作用所介导的 单独或联合应用于血管平滑肌细胞 CAMP途径的缓冲能力不足。建议的研究 将使用两种方法对潜在机制进行深入调查 完整的动物和体外细胞研究。具体目标是：1) 明确AII在肾脏阻力血管中的作用 高血压2)确定加压素对肾阻力的影响 遗传性高血压的血管及3)研究cAMP的相互作用 AII或AVP在肾阻力中的作用途径及血管收缩作用 遗传性高血压中的血管。研究将涉及全肾和 单个肾单位的体内研究，以及对新鲜分离的 组织和培养细胞评估第二信使信号转导。 将评估关键步骤，如受体的表达和与G的偶联 蛋白质，磷脂酶C刺激，IP3生成，钙通道 激活和钙库动员，以及蛋白激酶C的激活。 这种对血管活动显著异常的研究应该能提供 提供更完整的正常监管信息的新信息 机制以及控制系统中的缺陷可能导致或 导致遗传性高血压的发生。

DESCRIPTION: (Adapted from the Applicant's Abstract) The long range goal of this proposal is to better understand mechanisms regulating renal hemodynamics and glomerular function by hormonal paracrine and autacoid agents in health and disease. This proposal continues a focus on mechanisms of vascular reactivity and receptor signaling pathways in the renal microcirculation during development of genetic hypertension. A unique combination of coordinated studies of overlapping themes is designed to gain insight into regulatory mechanisms responsible for excessive renal vasoconstriction and increased tubulo-glomerular feedback activity in the spontaneously hypertensive rat (SHR). This proposal builds on the previous in vivo observations by the principal investigator, suggesting exaggerated renal vascular reactivity to angiotensin II (AII) in SHR which is primarily due to defective buffering afforded by vasodilator agents triggering the cAMP pathway. The primary abnormality in cAMP in SHR appears to be localized to the receptor-Gs-protein coupling. The enhanced renal vasoconstrictor response to vasopressin (AVP) also seen in SHR appears to be due to increased activity of the V1 AVP receptor. This proposal will continue to evaluate the central hypothesis that exaggerated renal vasoconstriction is mediated by direct actions of the vasoconstrictor agents on vascular smooth muscle cells either alone or in combination with a deficiency in the buffering capacity of the cAMP pathway. Proposed studies will conduct in depth investigation of the underlying mechanism using both intact animal and in vitro cells studies. The specific aims are: 1) To define the actions of AII on renal resistance vessels in genetic hypertension 2) To determine the effects of vasopressin on renal resistance vessels in genetic hypertension and 3) To investigate interactions of cAMP pathways and the vasoconstriction produced by AII or AVP in renal resistance vessels in genetic hypertension. Studies will involve whole kidney and single nephron in vivo studies, as well as in vitro work on freshly isolated tissue and cultured cells to evaluate second messenger signal transduction. Key steps will be assessed such as receptor expression and coupling with G proteins, phospho lipase C stimulation, IP3 generation, calcium channel activation and calcium store mobilization, and protein Kinase C activation. This search for significant abnormalities in vascular actions should provide new information providing a more complete understanding of normal regulatory mechanisms as well as defects in control systems that may cause or contribute to the development of genetic hypertension.