MICROPUNCTURE STUDY OF KIDNEY FUNCTION

肾功能的微穿刺研究

• 批准号: 2702067
• 负责人: WILLIAM J ARENDSHORST
• 金额: $ 31.95万
• 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/2702067
• 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） 这项建议是为了更好地了解调节肾脏的机制， 激素旁分泌和自分泌对血液动力学和肾小球功能影响 健康和疾病的代理人。 这项建议继续侧重于机制 血管反应性和受体信号通路在肾脏 微循环在遗传性高血压发展过程中的作用。 一个独特 重叠主题的协调研究的组合旨在获得 对过度肾功能的调节机制的深入了解 血管收缩和增加的肾小管-肾小球反馈活动， 自发性高血压大鼠（SHR）。 这一建议建立在以前的基础上， 主要研究者的体内观察结果表明， SHR的肾血管对血管紧张素II（AII）的反应性， 由于血管扩张剂提供的有缺陷的缓冲， cAMP途径。 SHR中cAMP的主要异常似乎是 定位于受体-Gs-蛋白偶联。 增强的肾 对加压素（AVP）的血管收缩反应也见于SHR， 这是由于V1 AVP受体的活性增加。 这项建议会 继续评估中心假设， 血管收缩由血管收缩剂的直接作用介导 对血管平滑肌细胞单独或与 cAMP途径的缓冲能力不足。 拟定研究 将使用这两种方法对潜在机制进行深入调查， 完整动物和体外细胞研究。 具体目标是：（1） 明确AII对肾阻力血管的作用， 2）确定加压素对肾阻力的影响 研究cAMP与血管内皮细胞的相互作用 途径和血管收缩产生的AII或AVP在肾阻力 血管遗传性高血压。 研究将涉及整个肾脏， 单个肾单位在体内的研究，以及在体外工作的新鲜分离 组织和培养的细胞以评估第二信使信号转导。 将评估关键步骤，如受体表达和与G 蛋白质类，磷脂酶C刺激，IP 3生成，钙通道 激活和钙库动员以及蛋白激酶C激活。 这种对血管活动显著异常的研究， 新的信息提供了一个更完整的了解正常的监管 机制以及控制系统中可能导致或 有助于遗传性高血压的发展。