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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 高血压的长期后果包括中风、心肾疾病和终末器官损伤，至少部分是由于肾素血管紧张素系统的全身性和肾内激活。 与血管紧张素II（Ang II）对肾小球细胞合成的肾素的抑制作用相反，在Ang II依赖性高血压中，远端肾单位段产生的肾素被刺激。 一种原肾素/肾素受体  远端肾单位段的（P）RR可能代表新一代血管紧张素肽。 远端肾单位段的肾素和（P）RR的相互作用可能代表了一种新的范式来解释肾内血管紧张素肽的生成增加，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，参与远端肾单位肾素的调节的机制，以及其与（P）RR的相互作用对Ang II依赖性高血压的发生和进展的贡献尚未阐明。本研究将探讨慢性Ang II输注介导的远端肾单位段中肾素调节的机制，以及在Ang II依赖性高血压中饮食盐变化期间肾素和（P）RR之间相互作用的意义，具体目标如下：第一章为了确定慢性肾内血管紧张素II含量增加是否通过直接激活血管紧张素II 1型受体或间接激活血管紧张素II 1型受体而增强远端肾单位的肾素产生，通过激活阿米洛利敏感性上皮钠通道和/或刺激醛固酮/特异性盐皮质激素受体刺激钠重吸收。 2)确定在Ang II依赖性高血压期间，饮食盐的变化对远端肾单位段中的肾素和（P）RR的影响;以及3）确定长期施用特异性肾素抑制剂阿利吉仑是否可以通过抑制远端肾单位段中的肾素和（P）RR来减轻慢性Ang II输注大鼠中的盐敏感性高血压和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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.