Renin receptor provoked renal inflammation

描述（由申请人提供）：肾素-血管紧张素系统（RAAS）是体液容量、电解质平衡和动脉压的主要生理调节剂。血管紧张素II（Ang II）是RAAS的主要效应肽，其大部分生物学作用归因于其对Ang II亚型-1受体（AT 1 R）的作用。血管紧张素Ⅱ还可刺激其2型受体（AT 2 R），主要产生血管舒张作用，抑制细胞肥大和增殖。然而，AT 2 R的功能并非完全未知。近年来发现了一种新的与肾素/原肾素受体结合的受体，命名为肾素/原肾素受体（renin/prorenin receptor，RR）。RR在生理学和病理学中的作用尚不清楚。我们实验室和其他实验室的初步数据表明，RR介导的特异性效应独立于Ang II。RR的刺激似乎诱导有丝分裂原活化蛋白激酶p44/p42的快速激活。目前，肾脏中RR的确切分布、调节和功能尚不清楚。本申请中提供的初步数据表明，肾素受体存在于肾小球和肾小管中，并受盐摄入量的调节。此外，有初步数据表明AT 1 R或AT 2 R与RR之间存在相互作用。本提案将在这些初步研究的基础上进行扩展，并将解决以下问题：1）调节RR表达的因素是什么？2)RR刺激产生的后果（功能）是什么？3)AT 1 R或AT 2 R与RR之间是否存在串扰？4)RR在肾血管性高血压中的作用是什么？该建议的主要假设是：肾脏RR有助于肾脏炎症和纤维化的发展。该提案的具体目标是：目的1：检验钠摄入量调节RR表达和活性的假设。目的II：验证AT 1 R或AT 2 R对RR表达和活性的调节作用。目的III：验证肾血管性高血压大鼠模型中RR表达和活性增加的假说。从这一建议中获得的信息将导致增加对高血压病理生理学的理解，并开发新的治疗方法。

DESCRIPTION (provided by applicant): The renin-angiotensin system (RAAS) is a major physiological regulator of body fluid volume, electrolyte balance, and arterial pressure. Majority of the biological actions of angiotensin II (Ang II), the principal effector peptide of the RAAS, are attributed to its action at the Ang II subtype-1 receptor (AT1R). Ang II also stimulates its subtype-2 receptor (AT2R) to mainly produce vasodilation and inhibition of cell hypertrophy and proliferation. However, the functions of the AT2R are not completely unknown. Recently, a new receptor that binds to renin/prorenin receptor was discovered and termed renin/prorenin receptor (RR). The role of the RR in physiology and pathology is unknown. Preliminary data from our laboratory' and others suggested that RR mediates specific effects independent of Ang II. Stimulation of RR seems to induce rapid activation of mitogen-activated protein kinases p44/p42. Currently, the exact distribution, regulation and functions of the RRs in the kidney are unknown. Preliminary data presented in this application suggest that renin receptor is present in the renal glomeruli and tubules and is regulated by salt intake. In addition, there are preliminary data to suggest an interaction between, AT1R or AT2R and the RR. This proposal will expand on these preliminary studies and will address the following questions: 1) What are the factors that regulate the expression of the RR? 2) What are the consequences (functions) resulting from RR stimulation? 3) Is there a cross talk between the AT1R or the AT2R and RR? 4) What is the role of RR in renovascular hypertension? The main hypothesis of this proposal is that: The renal RR contributes to development of renal inflammation and fibrosis. The specific aims for this proposal are: AIM 1: To test the hypothesis that sodium intake regulates RR expression and activity. AIM II: To test the hypothesis that AT1R or AT2R regulate RR expression and activity. AIM III: To test the hypothesis that RR expression and activity is increased in renovascular hypertension rat model. Information gained from this proposal will lead to increased understanding of the pathophysiology of hypertension and development of novel therapies for its management.