Natriuretic Mechanisms Uderlying Spontaneous Hypertension

描述(申请人提供)：原发性(主要)高血压影响25%的成年人口，是中风、心肌梗死、心力衰竭和终末期肾脏疾病的主要危险因素。自发性高血压大鼠(SHR)是一种近交系，随着年龄的增长而发生高血压，被广泛用作原发性高血压的模型。年轻的高血压前期自发性高血压患者表现出肾脏近端小管钠重吸收增加，其中正常的钠排泄是以肾脏灌流压升高为代价的。随着时间的推移，肾脏恢复到需要升高的血压，以便继续排泄正常的钠负荷。最终导致自发性高血压患者高血压的钠尿缺陷尚不清楚，将是目前应用的中心焦点。 在正常啮齿动物中，肾血管紧张素-2受体(AT2R)被证实在肾血管紧张素-1受体(AT1R)阻断和血管紧张素Ⅲ(Ang III)直接激动剂刺激下介导利钠作用。初步证据表明，AT2R必须移位到近端小管细胞的顶膜，才能介导利钠反应。在高血压自发性高血压患者中，肾脏AT1R阻断和Ang III刺激肾脏AT2R后，钠尿功能受损。目前尚不清楚SHR的利钠缺陷是否由肾近端小管AT2R易位引起，以及在该模型中这种缺陷是否对高血压的发生有重要作用，这些问题将在本应用中得到解答。同样，由于Ang III而不是血管紧张素II(Ang II)似乎是AT2R介导的肾脏钠尿的首选配体，负责产生和降解Ang III的酶也是重要的。这些酶分别为氨基肽酶A(APA)和氨基肽酶N(APN)，分别存在于肾近端小管细胞中。SHR是否存在APA或APN在肾近端小管细胞中的表达或活性缺陷也将被研究。 总而言之，这些研究的发现将阐明自发性高血压患者中存在的钠尿缺陷机制。识别这些缺陷对于我们理解人类高血压的发病机制是至关重要的。

DESCRIPTION (provided by applicant): Primary (essential) hypertension affects 25% of the adult population and constitutes a major risk factor for stroke, myocardial infarction, heart failure, and end-stage kidney disease. The spontaneously hypertensive rat (SHR) is an inbred strain that develops high blood pressure (BP) with increasing age and is widely used as a model of primary hypertension. Young, pre-hypertensive SHR exhibit increased renal proximal tubule sodium reabsorption, wherein normal sodium excretion is achieved only at the expense of elevated renal perfusion pressure. Over time, the kidneys reset to require elevated BP in order to continue to excrete a normal sodium load. The defects in natriuresis that ultimately lead to the initiation of hypertension in SHR are not known, and will be the central focus of the current application. In normal rodents, the renal angiotensin type-2 (AT2R) receptor has been shown to mediate natriuresis in response to renal angiotensin type-1 receptor (AT1R) blockade and direct agonist stimulation with angiotensin'III (Ang III). Preliminary evidence suggests that the AT2R must translocate to the apical membrane of proximal tubule cells in order to mediate the natriuretic response. In hypertensive SHR, natriuresis is defective in response to renal AT1R blockade and Ang III stimulation of the renal AT2R. Whether the natriuretic defects in SHR are due to alterations in renal proximal tubule AT2R translocation is unknown, and whether this defect is important to the initiation of hypertension in this model remains are questions that will be answered in this application. Likewise, because Ang III and not angiotensin II (Ang II) appears to be the preferred ligand of renal AT2R-mediated natriuresis, the enzymes responsible for generating and degrading Ang III are also of importance. These enzymes, aminopeptidase A (APA) and aminopeptidase N (APN), repspectively are present in renal proximal tubule cells. Whether SHR have defective APA or APN expression or activity in renal proximal tubule cells will also be investigated. Together, the findings from these studies will elucidate defective natriuretic mechanisms that are present in SHR. Identification of these defects are essential to our understanding of the pathogenesis of essential hypertension in humans.