Renal Vascular Reactivity in Genetic Hypertension

遗传性高血压中的肾血管反应性

• 批准号: 7472526
• 负责人: WILLIAM J ARENDSHORST
• 金额: $ 50.55万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472526
• 关键词: ADP-ribosyl Cyclase; AGTR2 gene; Accounting; Adult; Affect; Affinity; Age; Agonist; Animals; Area; Attenuated; Binding; Blood Vessels; Blood Volume; Blood flow; Buffers; Caliber; Cardiovascular system; Cells; Chemosensitization; Chronic; Competitive Binding; Constriction procedure; Defect; Development; Dilator; Disease; Dose; Elements; Endothelin-1; Enhancers; Enzymes; Equilibrium; Event; Excretory function; Feedback; Figs - dietary; Flowmetry; Foundations; Functional disorder; Future; G-Protein-Coupled Receptors; Glomerular Filtration Rate; Goals; Health; Hormonal; Hydrogen Peroxide; Hypertension; Immunoblotting; In Vitro; Inbred SHR Rats; Inbred WKY Rats; Indium; Individual; Infusion procedures; Injection of therapeutic agent; Inositol; Investigation; Isoprostanes; Kidney; Knowledge; Measures; Mediating; Mediator of activation protein; Messenger RNA; Metabolism; Microcirculation; Microscopy; Modeling; Molecular; NAD(P)H oxidase; Natriuresis; Nitric Oxide; Organ; Oxidative Stress; Pathway interactions; Perfusion; Peroxonitrite; Phase; Phospholipase C; Plasma; Play; Prevention; Production; Prostaglandins; Protein Isoforms; Proteins; Reaction; Receptor Signaling; Regulation; Relative (related person); Renal Blood Flow; Renin; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sodium; Superoxide Dismutase; Superoxides; System; Testing; Thromboxane Receptor; Thromboxanes; Time; Tissues; Transcriptional Activation; Ultrasonics; Up-Regulation; Vascular resistance; Vasoconstrictor Agents; Vasodilator Agents; Vasomotor; Western Blotting; Work; arteriole; autocrine; base; critical developmental period; density; early onset; experience; familial hypertension; feeding; human AKAP13 protein; in vivo; innovation; insight; isoprostaglandin F2alpha type-III; kidney vascular structure; mimetics; neutrophil cytosol factor 67K; paracrine; pressure; prevent; radioligand; receptor; receptor coupling; receptor density; renal NAD(P)H oxidase; renal artery; response; tempol; vasoactive agent; vasoconstriction; ward

DESCRIPTION (provided by applicant): A balance between vasoconstrictor and dilator systems plays a critical role in the kidney, setting the blood flow, glomerular filtration rate and sodium excretion. Our goal is to gain a better understanding of hormonal, paracrine and autocrine control of vasomotor tone in the renal microcirculation in health and disease, with particular emphasis on regulation of vascular reactivity and receptor signaling pathways in preglomerular resistance arterioles in genetic hypertension. Our previous studies on hypertensive adult spontaneously hypertensive rats (SHR) indicate that excessive renal vasoconstriction is mediated by an imbalance of actions of the vasoconstrictors Ang II and thromboxane (TxA2) and vasodilator systems (prostanoids, nitric oxide (NO)). Our recent work indicates that Ca2+ and contractile responses are mediated by signaling cascade involving ADP ribosyl cyclase and Ca2+ release from ryanodine receptors (RyR). In new studies, we shall focus on pro-hypertensive events before the development of hypertension which are most likely to be causative. We shall characterize interactions among Ang II, endothelin-1 (ET1), and TxA2 and their stimulation of NAD(P)H oxidase and superoxide anion (O2-) on vasomotor tone and Ca2+ signaling in afferent arterioles of prehypertensive 4-5-wk-old SHR. We hypothesize that exaggerated reductions in renal blood flow (RBF) in SHR are mediated by direct actions of constrictor agents on VSMC, either alone, due to enhanced receptor density or post-receptor signaling, or in concert with deficient buffering by the vasodilator NO. We propose that vasoconstriction favored by O2- is due to interactions with Ca2+ signaling in VSMC plus scavenging of NO. Specific aims will test the hypotheses that: 1) Renal vascular reactivity to Ang II, ET1 and TxA2 is exaggerated in prehypertensive SHR and that the O2-, ADP ribosyl cyclase, RyR and Ca2+ mobilization pathway plays a critical role; 2) Ca2+ signaling in afferent arterioles is enhanced in response to Ang II, ET1 and TxA2 and that the O2- / ADP ribosyl cyclase / RyR pathway is central; and 3) mRNA and protein levels of receptors for Ang II, ET1, and TxA2 and NAD(P)H subunits are up-regulated in the preglomerular vasculature of 4-5-wk-old SHR. Innovative complementary in vivo RBF studies of integrative pathophysiology and in vitro studies of cellular effector signal transduction in isolated arterioles will provide insight into pro-hypertensive mechanisms responsible for renal vasoconstriction in prehypertensive SHR.

描述（由申请人提供）：血管收缩和扩张系统之间的平衡在肾脏中起着关键作用，可设定血流量、肾小球滤过率和钠排泄。我们的目标是更好地了解激素，旁分泌和自分泌控制的血管紧张素在肾脏微循环的健康和疾病，特别强调在遗传性高血压的肾小球前阻力小动脉的血管反应性和受体信号通路的调节。我们先前对高血压成年自发性高血压大鼠（SHR）的研究表明，过度的肾血管收缩是由血管收缩剂Ang II和血栓素（TxA 2）和血管舒张系统（前列腺素，一氧化氮（NO））的作用失衡介导的。我们最近的工作表明，Ca ~（2+）和收缩反应是由ADP核糖环化酶和RyR释放Ca ~（2+）的信号级联介导的。在新的研究中，我们将重点关注高血压发生前的促高血压事件，这些事件最有可能是高血压的病因。我们将描述血管紧张素II，内皮素-1（ET-1）和TxA 2之间的相互作用及其对NAD（P）H氧化酶和超氧阴离子（O2-）的刺激对高血压前期4-5周龄SHR传入小动脉血管紧张素和Ca 2+信号的影响。我们假设SHR肾血流量（RBF）的过度减少是由收缩剂对VSMC的直接作用介导的，无论是单独的，还是由于受体密度增加或受体后信号传导，或与血管扩张剂NO缓冲不足一致。我们认为O2-促进的血管收缩是由于与Ca 2+的相互作用VSMC中的信号传导加上NO的清除。具体目标将测试以下假设：1）高血压前期SHR肾血管对Ang Ⅱ、ET 1和TxA 2的反应性增强，（2）Ang Ⅱ、ET 1和TxA 2可增强传入小动脉内Ca ~（2+）信号，其中O ~（2-）/ ADP核糖环化酶/ RyR通路起着重要作用;（3）4-5周龄SHR肾小球前血管中Ang Ⅱ、ET 1、TxA 2受体和NAD（P）H亚单位的mRNA和蛋白水平上调。创新的补充在体内RBF研究的综合病理生理学和在离体小动脉的细胞效应信号转导的体外研究将提供洞察促高血压机制负责高血压前期SHR的肾血管收缩。