Renal Vascular Reactivity in Genetic Hypertension

描述(申请人提供)：本研究的长期目标是 更好地了解控制血管反应性的机制 激素类、旁分泌类和类金盏花素对健康人肾微循环的影响 和疾病。我们将继续把研究重点放在血管的调节上 肾小球前血管系统中的反应性和受体信号通路。一个 体内和体外协调治疗方法的独特结合 重叠主题旨在深入了解监管机制 对幼年自发性高血压大鼠肾血管收缩的影响 (SHR)。我们之前的研究表明，过度的肾脏血管收缩 与高血压的发展有关，并由异常的 血管紧张素-II(Ang-II)、血管加压素的作用平衡 (AVP)、血栓素A_2(TXA_2)和血管扩张系统(前列腺素、一氧化氮) 氧化物)。在拟议的研究中，我们将描述其他血管收缩药的特征 系统，如α-肾上腺素能神经系统和内皮素(ET)，以及 它们在年轻的自发性高血压患者中产生增强的肾脏血管舒缩张力的机制。我们 将检验夸大的血管收缩是中介的中心假说 通过缩窄剂对血管平滑肌细胞的直接作用， 要么单独，由于受体密度增强或受体后信号转导，要么在 合并血管扩张剂缓冲能力不足 前列腺素。具体目标是：i)评估活体肾血管反应性 明确去甲肾上腺素、内皮素、前列腺素和反应性激素的作用 氧物种在年轻自发性高血压大鼠肾血管过度收缩中的作用：II)评估 体内和体外细胞信号转导途径的研究 血管紧张剂的中介作用及其作用机制 幼年自发性高血压大鼠肾血管舒缩张力增强；III)体内调节研究 Ang II、AVP、TXA2、A1-肾上腺素能和ET受体；以及IV)定义这些受体的作用 酪氨酸激酶和MAP/ERK信号通路与肾血管肥大的关系 年轻自发性高血压患者对缩窄剂的反应性。我们将评估关键信号 受体mRNA表达和蛋白结合的转导步骤，以及 通过与细胞内途径偶联来刺激胞内钙 动员和招募进入渠道。我们对有重大意义的 血管活动的异常应该提供重要的新信息 促进了对正常调控机制的更全面的理解 控制器中可能导致或有助于开发的缺陷 遗传性高血压。

DESCRIPTION (provided by applicant): The long-range goal of this research is to gain a better understanding of mechanisms that control vascular reactivity in the renal microcirculation by hormonal, paracrine and autacoid agents in health and disease. We will continue to focus our studies on regulation of vascular reactivity and receptor signaling pathways in the preglomerular vasculature. A unique combination of coordinated in vivo with in vitro approaches of overlapping themes is designed to gain insight into regulatory mechanisms responsible for renal vasoconstriction in young spontaneously hypertensive rats (SHR). Our previous studies indicate that excessive renal vasoconstriction is associated with the development of hypertension and is mediated by an abnormal balance of actions of vasoconstrictor angiotensin II (Ang II), vasopressin (AVP), and thromboxane (TxA2) and vasodilator systems (prostanoids, nitric oxide). In the proposed studies, we will characterize other vasoconstrictor systems, such as a-adrenergic nervous system and endothelin (ET), and the mechanisms by which they produce enhanced renal vasomotor tone in young SHR. We will test the central hypothesis that exaggerated vasoconstriction is mediated by direct actions of the constrictor agents on vascular smooth muscle cells, either alone, due to enhanced receptor density or postreceptor signaling, or in combination with a deficiency in the buffering capacity of vasodilator prostanoids. Specific aims are: I) Evaluate renal vascular reactivity in vivo to define the contribution of norepinephrine, ET, prostanoids and reactive oxygen species in exaggerated renal vasoconstriction in young SHR; II) Assess cellular signaling in vivo and in vitro to determine signaling pathways mediating actions of vasoconstrictor agents and mechanisms responsible for enhanced renal vasomotor tone in young SHR; III) Investigate in vivo regulation of Ang II, AVP, TxA2, a1-adrenergic, and ET receptors; and IV) Define the roles of tyrosine kinase and MAP/ERK kinase pathways to exaggerated renal vascular reactivity to constrictor agents in young SHR. We will evaluate key signal transduction steps from receptor mRNA expression and protein binding, and coupling with intracellular pathways to stimulate cytosolic calcium via mobilization and recruitment of entry channels. Our search for significant abnormalities in vascular actions should provide important new information that advances a more complete understanding of normal regulatory mechanisms and defects in controllers that may cause or contribute to the development of genetic hypertension.