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，决定着血流、肾小球滤过率和钠的排泄。我们的目标是更好地了解健康和疾病患者肾脏微循环中激素、旁分泌和自分泌对血管运动张力的控制，特别是在遗传性高血压的肾小球前阻力小动脉中血管反应性和受体信号通路的调节。我们以前对高血压成年自发性高血压大鼠(SHR)的研究表明，过度的肾脏血管收缩是由血管收缩因子Ang II和血栓素A_2(TXA_2)和血管扩张系统(前列腺素、一氧化氮(NO))的作用失衡所致。我们最近的工作表明，钙离子和收缩反应是通过ADP核糖环化酶和兰尼定受体(RyR)释放钙的信号级联来介导的。在新的研究中，我们将重点放在高血压发展之前的高血压前期事件，这些事件最有可能是病因。我们将在高血压前期4-5周龄自发性高血压大鼠(SHR)研究血管紧张素II(Ang II)、内皮素-1(ET1)和血栓素A2(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-)对血管运动张力和钙信号的刺激作用。我们推测，自发性高血压大鼠肾血流量(RBF)的夸大减少是由缩血管药对VSMC的直接作用所介导的，要么是由于受体密度增加或受体后信号转导，要么是与血管扩张剂NO缓冲不足协同作用。我们认为，O2-有利于血管收缩是由于与VSMC内钙信号的相互作用和NO的清除。特定的AIMS将验证以下假设：1)高血压前期SHR肾血管对Ang II、ET1和TXA2的反应性被夸大，O2-、ADP核糖环化酶、RyR和钙动员途径起关键作用；2)Ang II、ET1和TXA2增强传入小动脉的钙信号，O2-/ADP核糖环化酶/RyR通路是中枢的；3)4-5周龄SHR肾小球前血管中Ang II、ET1、TXA2和NAD(P)H亚基受体的mRNA和蛋白水平上调。综合病理生理学的体内RBF创新互补研究和体外细胞效应信号转导研究将为高血压前期自发性高血压患者肾血管收缩的亲高血压机制提供洞察力。

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.