MICROPUNCTURE STUDY OF KIDNEY FUNCTION

肾功能的微穿刺研究

• 批准号: 2910469
• 负责人: WILLIAM J ARENDSHORST
• 金额: $ 35.45万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2910469
• 关键词: angiotensin II; arginine vasopressin; atrial natriuretic peptide; biological signal transduction; chemoreceptors; familial hypertension; hemodynamics; hormone receptor; hormone regulation /control mechanism; kidney circulation; micropuncture; molecular pathology; receptor coupling; receptor expression; renal glomerulus; saluresis; spontaneous hypertensive rat; tissue /cell culture; vascular smooth muscle; vasoconstriction

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.

描述：（改编自申请人的摘要）长期目标 该建议是为了更好地了解调节肾脏的机制 激素旁分泌和自体激素影响血流动力学和肾小球功能 健康和疾病的代理人。 该提案继续关注机制 肾血管反应性和受体信号通路的研究 遗传性高血压发展过程中的微循环。 一个独特的 重叠主题的协调研究的结合旨在获得 深入了解肾过度的调节机制 血管收缩和肾小球反馈活性增加 自发性高血压大鼠（SHR）。 该提案建立在之前的提案基础上 主要研究者的体内观察表明夸大了 SHR 中肾血管对血管紧张素 II (AII) 的反应性主要是 由于血管扩张剂提供的缓冲缺陷导致 cAMP 途径。 SHR 中 cAMP 的主要异常似乎是 定位于受体-Gs-蛋白质偶联。 增强肾功能 SHR 中也出现了对加压素 (AVP) 的血管收缩反应，似乎是 由于 V1 AVP 受体活性增加。 该提案将 继续评估夸大肾功能的中心假设 血管收缩是由血管收缩剂的直接作用介导的 单独或与血管平滑肌细胞联合作用 cAMP 通路的缓冲能力不足。 拟议的研究 将利用两者对潜在机制进行深入研究 完整的动物和体外细胞研究。 具体目标是： 1) 定义 AII 对肾阻力血管的遗传作用 高血压 2) 确定加压素对肾抵抗的影响 遗传性高血压中的血管和 3) 研究 cAMP 的相互作用 肾抵抗中 AII 或 AVP 产生的途径和血管收缩 遗传性高血压的血管。 研究将涉及整个肾脏和 单个肾单位的体内研究，以及新鲜分离的体外研究 组织和培养细胞以评估第二信使信号转导。 将评估关键步骤，例如受体表达和与 G 的偶联 蛋白质、磷脂酶 C 刺激、IP3 生成、钙通道 激活和钙储存动员，以及蛋白激酶 C 激活。 对血管活动显着异常的搜索应该提供 新信息提供了对正常监管更全面的了解 机制以及控制系统中的缺陷可能会导致或 有助于遗传性高血压的发生。