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，是中风、心肌梗死、心力衰竭和终末期肾病的主要危险因素。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表现为肾近端小管钠重吸收增加，其中正常的钠排泄仅以肾脏灌注压升高为代价。随着时间的推移，肾脏重新调整为需要升高的血压，以继续排泄正常的钠负荷。钠尿缺陷最终导致SHR中高血压的开始尚不清楚，这将是当前应用的中心焦点。

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.