Autocoids in Hypertension: Pathogenesis and End Organ Damage

描述(由申请人提供)： 这个PPG成立于1982年9月。中心主题是“研究血管活性系统(自分泌、旁分泌、旁分泌和内分泌)在调节肾功能和血压(BP)以及调节终末器官损伤(EOD)中的作用”。需要检验的一般假设是，在促进水和钠保持、高血压和EOD的系统之间存在平衡，包括血管紧张素II(Ang II)、前列腺素、活性氧和炎症，以及拮抗这些影响的系统，如Ac-SDKP、Ang II 2型受体(AT2)的激活、激动素、NO、PGE2/Ep4，以及新发现的连接小管和传入小动脉(CTGF)之间的串扰，这可能参与利钠和肾损伤。这种有利于前者的平衡改变是导致水和钠滞留以及高血压和EOD的发生的原因，而有利于后者的这种平衡改变具有治疗作用。我们将使用 分子、生理和药理学方法研究高血压大鼠亚细胞、细胞和分离器官水平的血管活性系统以及不同转基因和 基因敲除小鼠。我们将主要以Dahl盐敏感大鼠(Dahl SS)和AngⅡ诱导的高血压大鼠为模型。在项目I中，我们将利用Dahl SS大鼠，研究N-乙酰-丝氨酰-天冬氨酰-赖氨酰-脯氨酸是否通过降低获得性免疫来保护EOD。在项目II中，我们将研究环氧合酶-2的表达和通过EP4受体产生的前列腺素E_2是否对血管紧张素Ⅱ诱导的高血压的EOD具有保护作用。在项目III中，使用Dahl SS大鼠，我们将研究CTGF是否通过传入动脉扩张和毛细血管肾小球压力增加而导致肾小球损伤。在项目IV中，使用Dahl SS大鼠，我们将研究肾脏粗大升支AT2信号的减少是否参与高血压的发病机制。四核。行政(A)、分析和形态(B)、突变小鼠(C)和生物统计学(D)将支持研究人员的科学努力。TE PPG整合了我们的努力、协作、想法和专业知识的共享，从而加快了对高血压和排泄物病因的知识获取。

DESCRIPTION (provided by applicant): This PPG was started in September, 1982. The central theme is "the study ofthe role of vasoactive systems (autocrine, juxtacrine, paracrine and endocrine) in the regulation of renal function and blood pressure (BP) and mediation of end organ damage (EOD)". The general hypothesis to be tested is that there is a balance between systems that promote water and sodium retention, hypertension and EOD, including Angiotensin II (Ang II), prostanoids, reactive oxygen species and inflammation, and systems that antagonize these effects like Ac-SDKP, activation of the Ang II type 2 receptor (AT2), kinins, NO, PGE2/EP4, and the newly discovered cross-talk between the connecting tubule and the afferent arteriole (CTGF) which may participate in both natriuresis and renal damage. Alterations of this balance in favor of the former are responsible for retention of water and sodium and development of hypertension and EOD, while alterations of this balance in favor of the latter have therapeutic effects. We will use molecular, physiological, and pharmacological approaches' to study vasoactive systems at the subcellular, cellular, and isolated organ levels in hypertension in rats and various transgenic and gene knockout mice. We will mainly use Dahl salt-sensitive rats (Dahl SS) and Ang ll-induced hypertensive rats as models. In Project I, using Dahl SS rats, we will study whether N-acetyl-seryl-aspartyl-lysyl-proline protects against EOD by decreasing adaptive immunity. In Project II we will study whether expression of cyclooxygenase-2 and generation of PGE2 via the EP4 receptor protects against EOD in Ang ll-induced hypertension. In Project III, using Dahl SS rats, we will study whether CTGF causes glomerular damage via afferent arterole dilatation and increases in capillary glomerular pressure. In Project IV, using Dahl SS rats, we will study whether a decrease in the renal thick ascending limb AT2-signaling participates in the pathogenesis of hypertension. Four cores. Administrative (A), Analytical and Morphological (B), Mutant Mouse (C), and Biostatistics (D) will support the scientific efforts of the investigators. Te PPG provides integration of our efforts, collaboration, sharing of ideas and expertise, thus accelerating acquisition of knowledge on the causes of hypertension and EOD.