Renal Vascular Reactivity in Genetic Hypertension

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至关重要的作用，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健康和疾病中肾脏微循环血管舒缩张力的激素、旁分泌和自分泌控制，特别强调遗传性高血压患者肾小球前抵抗性小动脉血管反应性和受体信号通路的调节。我们之前对成年自发性高血压大鼠（SHR）的研究表明，肾脏血管过度收缩是由血管收缩剂Ang II和血栓素（TxA2）以及血管扩张系统（前列腺素、一氧化氮（NO））的不平衡所介导的。我们最近的研究表明，Ca2+和收缩反应是由信号级联介导的，涉及ADP核糖基环化酶和ryanodine受体（RyR）的Ca2+释放。在新的研究中，我们将把重点放在高血压发生前的促高血压事件上，这是最有可能导致高血压的原因。我们将描述Ang II、内皮素-1 （ET1）和TxA2之间的相互作用，以及它们对NAD(P)H氧化酶和超氧阴离子（O2-）对高血压前期SHR传入小动脉血管舒缩张力和Ca2+信号的刺激。我们假设SHR中肾血流量（RBF）的过度减少是由收缩剂对VSMC的直接作用介导的，或者单独作用，由于受体密度或受体后信号的增强，或者与血管扩张剂NO的缓冲不足相一致。我们认为O2-有利于血管收缩是由于与VSMC中Ca2+信号的相互作用以及NO的清除。具体目的将验证以下假设：1)高血压前期SHR中肾血管对Ang II、ET1和TxA2的反应性被夸大，O2-、ADP核糖素环化酶、RyR和Ca2+动员途径起关键作用；2)传入小动脉中的Ca2+信号在Ang II、ET1和TxA2的作用下增强，O2- / ADP核糖素环化酶/ RyR通路是中心通路；3) 4-5周龄SHR肾小球前血管中Ang II、ET1、TxA2和NAD(P)H亚基受体mRNA和蛋白水平上调。创新性互补的体内RBF综合病理生理学研究和离体小动脉细胞效应信号转导的体外研究将为高血压前期SHR中肾血管收缩的促高血压机制提供见解。

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.