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

远端肾单位肾素

• 批准号: 8360257
• 负责人: Minolfa C Prieto
• 金额: $ 20.65万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360257
• 关键词: Aldosterone; Angiotensin II; Angiotensins; Attenuated; Biology; Centers of Research Excellence; Chronic; Development; Disease; Distal; Funding; Generations; Grant; Hypertension; Infusion procedures; Injury; Juxtaglomerular Cell; Kidney; Mediating; National Center for Research Resources; Nephrons; Organ; Oxidative Stress; Peptides; Principal Investigator; Production; Rattus; Receptor, Angiotensin, Type 1; Regulation; Renal Hypertension; Renin; Renin-Angiotensin System; Research; Research Infrastructure; Resources; Signal Pathway; Sodium; Sodium Chloride; Source; Stroke; United States National Institutes of Health; aliskiren; cost; epithelial amiloride-sensitive sodium channel; inhibitor/antagonist; prorenin receptor; receptor

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 高血压的长期后果，包括中风，心脏疾病和最终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内部激活。 与抑制性作用相反，即血管紧张素II（ANG II）对由近胶质细胞合成的肾素施加的肾素施加的抑制作用，在Ang II依赖性高血压中刺激了在远端肾单位段中产生的肾素。 促肾素/肾素受体远端肾单位段（P）RR可能代表新一代的血管紧张素肽。 肾素和（p）RR在远端肾单位段的相互作用可能代表一种新的范式，以解释血管紧张素肽的肾内产生增加，还可能有助于解释局部信号传导途径的激活，导致肾脏损伤和高血压。 然而，涉及远端肾单肾肾素调节的机制，其与（P）RR相互作用对ANG II依赖性高血压的发展和进展的贡献都没有得到阐明。 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通过激活氨基胺敏感的上皮钠通道和/或醛固酮/特异性矿物质类药物受体的激活，通过激活钠敏感性上皮钠通道来间接刺激钠。 2）确定饮食中盐变化对ANG II依赖性高血压期间远端肾单位段中肾素和（P）RR的影响； 3）为了确定特异性肾素抑制剂aliskiren的长期给药是否可以通过抑制远端肾肾上腺段中抑制肾素和（p）RR来减轻慢性ANG II污染大鼠的盐敏感性高血压和相关的肾上部氧化应激和肾脏损伤。