DISTAL NEPHRON RENIN & PRORENIN RECEPTOR IN ANG II-DEPENDANT HYPERTENSION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 高血压的长期后果包括中风、心脏肾脏疾病和终末器官损害，至少部分是由于肾素血管紧张素系统的全身和肾内激活。与血管紧张素II(Ang II)对肾小球旁细胞合成肾素的抑制作用不同，Ang II依赖型高血压患者肾素在肾小球远端段的合成受到刺激。肾素原/肾素受体(P)RR可能代表新一代血管紧张素肽。肾素与肾小球末端(P)RR的相互作用可能代表了一种解释肾内血管紧张素肽生成增加的新范式，也可能有助于解释导致肾损伤和高血压的局部信号通路的激活。然而，远端肾小球肾素的调节机制及其与(P)RR的相互作用在血管紧张素Ⅱ依赖型高血压的发生发展中的作用尚未阐明。本研究将探讨慢性Ang II输注对肾素在远端肾小管节段的调节机制，以及在Ang II依赖性高血压患者饮食盐变化过程中肾素与(P)RR之间的相互作用的意义，目的在于：1)确定慢性肾内Ang II含量增加是否直接通过激活Ang II 1型受体或通过激活阿米洛利敏感的上皮性钠通道和/或刺激醛固酮/特异性盐皮质激素受体而间接刺激钠的重吸收来促进远端肾小管肾素的产生。2)研究饮食盐的变化对Ang II依赖型高血压大鼠肾脏肾素和肾远端(P)RR的影响；3)研究长期应用特定肾素抑制剂Aliskiren能否通过抑制肾素和肾远端(P)RR而减轻慢性Ang II依赖大鼠的盐敏感性高血压及相关的肾内氧化应激和肾损伤。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Long-term consequences of high blood pressure including stroke, cardiorenal disease, and end-organ damage are, at least in part, due to a systemic and intrarenal activation of the renin angiotensin system. In contrast to the inhibitory effect that angiotensin II (Ang II) exerts on renin synthesized by juxtaglomerular cells, renin produced in distal Nephron segments is stimulated in Ang II-dependant hypertension. A pro-renin/renin receptor  the (P)RR at the distal Nephron segments may represent a new generation of angiotensin peptides. Interaction of renin and (P)RR at the distal Nephron segments may represent a new paradigm to explain the increased intrarenal generation of angiotensin peptides and may also help to explain the activation of local signaling pathways contributing to renal injury and hypertension. However, the mechanisms involved in the regulation of distal Nephron renin, neither the contribution of its interaction with the (P)RR to the development and progression of the Ang II-dependant hypertension have been elucidated. This study will investigate the mechanisms responsible for the regulation of renin in the distal Nephron segments mediated by the chronic Ang II infusions and the implications of the interaction between renin and (P)RR during changes of dietary salt in Ang II-dependant hypertension by targeting the following specific aims: 1) To determine if chronically increased intrarenal Ang II content enhances renin production in the distal Nephron directly by activation of Ang II type 1 receptor or indirectly by stimulation of sodium Reabsorption via activation of amiloride-sensitive epithelial sodium channels and/or stimulation of aldosterone/specific mineralcorticoid receptors. 2) To determine the effects of changes in dietary salt on renin and the (P)RR in distal Nephron segments during Ang II-dependant hypertension; and 3) To determine whether chronic administration of the specific renin inhibitor Aliskiren, can attenuate the salt sensitivity hypertension and related intrarenal oxidative stress and kidney injury in chronic Ang II-infused rats by inhibition of renin and (P) RR in distal Nephron segments.