PLEIOTROPIC EFFECTS OF PRORENIN RECEPOR IN COLLECTING DUCT AND INTRARENAL RAS ACTIVATION

描述（由申请人提供）：糖尿病和高血压是慢性肾脏疾病的两个主要风险因素。肾内肾素-血管紧张素系统（调节血压和水平衡的激素系统，RAS）的不适当激活大大增加了肾损伤的风险和进展。目前针对RAS的治疗只能减缓而不是阻止慢性肾脏疾病的进展。因此，我们迫切需要了解激活该系统并导致血压升高和肾损伤的机制，以开发新的治疗靶点来控制终末期器官损伤的进展。我们的长期目标是确定在集合管中新发现的前肾素受体在高血压和肾损伤的发病机制中的作用，并引入一个具有范式挑战性的概念，解释集合管中前肾素受体和前肾素之间的相互作用，强调这种相互作用的功能作用。 在糖尿病和高血压中钠重吸收、血压和肾纤维化的发展和进展的调节中的相互作用。我们的核心假设是， 在高血压和高血糖症期间，在集合管中的原肾素受体和原肾素之间的相互作用通过既依赖于又不依赖于血管紧张素II（肾素-血管紧张素系统的主要效应激素）的机制而导致血压升高和肾损伤的发展和进展。将针对以下具体目的对该假设进行检验：（1）证明前肾素受体是激活集合管中产生的前肾素所必需的;（2）确定血管紧张素II依赖性高血压期间集合管中前肾素和可溶性前肾素受体之间相互作用的功能后果;和（3）证明在链脲佐菌素诱导的高血糖期间，膜结合的前肾素受体对集合管细胞的前肾素依赖性激活导致肾纤维化。我们将使用垂直和创新的方法来实现这些具体目标，其中包括使用我们实验室开发的独特小鼠模型进行体内和体外实验，该模型对集合管中的前肾素受体进行特定的基因缺失。实验将使用综合生理学、分子学和组织学方法进行评估。这项研究的成功完成具有重要意义，因为研究结果将提供明确的体内证据，证明前肾素受体在集合管中的功能作用，这将为靶向该受体的新型药物的产生提供理论依据。了解这种新途径的机制将与公共卫生相关，因为它将允许优化与增强的前肾素受体-前肾素相互作用相关的疾病（如高血压、糖尿病和先兆子痫）的治疗。

DESCRIPTION (provided by applicant): Diabetes and hypertension are two major risk factors for chronic kidney disease. Inappropriate activation of the intrarenal renin-angiotensin system (the hormone system that regulates blood pressure and water balance, RAS) substantially increases risk and progression to renal injury. Current treatments targeting the RAS only slow, rather than halt the progression to chronic kidney disease. Therefore, we urgently need to understand the mechanisms which activate this system and lead to increased blood pressure and renal injury in order to develop new therapeutic targets to control the progression to end-stage organ damage. Our long- term goal is to define the contributions of the newly discovered prorenin receptor in the collecting duct to the pathogenesis of hypertension and renal injury and to introduce a paradigm-challenging concept which explains the interaction between the prorenin receptor and prorenin in the collecting duct which highlights the functional roles of this interaction in the regulation of sodium reabsorption, blood pressure, and development and progression of renal fibrosis in diabetes mellitus and hypertension. Our central hypothesis is that during hypertension and hyperglycemia, the interaction between the prorenin receptor and prorenin in the collecting duct contribute to increased blood pressure and to the development and progression to renal injury by mechanisms that are both dependent and independent of angiotensin II, the major effector hormone of the renin-angiotensin system. This hypothesis will be tested addressing the following specific aims: (1) Demonstrate that the prorenin receptor is required for the activation of prorenin produced in the collecting ducts; (2) Determine the functional consequences of the interaction between prorenin and soluble prorenin receptor in the collecting duct during angiotensin II-dependent hypertension; and (3) Demonstrate that prorenin-dependent activation of membrane bound prorenin receptor to collecting duct cells leads to renal fibrosis during Streptozotocin-induced hyperglycemia. We will attain these specific aims using a vertical and innovated approach which will include in vivo and in vitro experiments using a unique mouse model developed by our laboratory with a specific genetic deletion of the prorenin receptor in the collecting duct. Experiments will be assessed using integrated physiological, molecular and histological methodologies. The successful completion of the research proposed is of great significance because findings will provide definitive in vivo evidence of the functional role of the prorenin receptor in the collecting duct, which will providea rationale for the generation of novel drugs targeting this receptor. Understanding the mechanism of this novel pathway will be of relevance to public health because it will allow the optimization of treatment in conditions associated with augmented prorenin receptor-prorenin interaction such as hypertension, diabetes, and preeclampsia.