Natriuretic Mechanisms Uderlying Spontaneous Hypertension

描述（由申请人提供）：原发性（原发性）高血压影响25%的成年人群，并构成中风、心肌梗死、心力衰竭和终末期肾病的主要风险因素。自发性高血压大鼠（SHR）是一种随年龄增长而发生高血压的近交系，被广泛用作原发性高血压的模型。年轻的高血压前期SHR表现出增加的肾近端小管钠重吸收，其中正常的钠排泄仅以升高的肾灌注压为代价来实现。随着时间的推移，肾脏重置为需要升高的血压，以继续排泄正常的钠负荷。最终导致SHR高血压发生的尿钠排泄缺陷尚不清楚，这将是当前应用的中心焦点。 在正常啮齿类动物中，肾血管紧张素2型（AT2R）受体已被证明介导尿钠排泄，以响应肾血管紧张素1型受体（AT1R）阻断和血管紧张素III（Ang III）的直接激动剂刺激。初步证据表明，AT2R必须易位到近端小管细胞的顶膜，以介导利钠反应。在高血压SHR中，尿钠排泄在对肾脏AT1R阻断和肾脏AT2R的Ang III刺激的反应中是缺陷的。SHR中的利钠素缺陷是否是由于肾近端小管AT2R易位的改变是未知的，并且在该模型中这种缺陷是否对高血压的起始很重要仍然是将在本申请中回答的问题。同样地，因为血管紧张素III而不是血管紧张素II（Ang II）似乎是肾AT2R介导的尿钠排泄的优选配体，所以负责产生和降解Ang III的酶也是重要的。这些酶，氨肽酶A（阿帕）和氨肽酶N（APN），存在于肾近曲小管细胞。SHR是否有缺陷的阿帕或APN的表达或活性在肾近曲小管细胞也将被调查。 总之，这些研究的结果将阐明SHR中存在的有缺陷的利钠机制。这些缺陷的鉴定对于我们理解人类原发性高血压的发病机制至关重要。

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.