ANGIOTENSIN RECEPTOR TOPOLOGY AND FUNCTION

描述（改编自申请人的摘要）： 肾小管（PT）通过重吸收盐在体内平衡中起重要作用 和水，但经常暴露于毒性和缺血性损伤，因此 不断地受到伤害和修复。 事实上，PT损伤是 肾衰竭的症状 PT含有完整的肾素-血管紧张素系统（RAS）， 产生内源性血管紧张素II（Ang II）。 血管紧张素转换酶 抑制剂有效减缓慢性肾功能不全的进展， 可减轻肾小管间质损伤。 因此，RAS及其 血管紧张素Ⅱ可能在PT损伤和修复中发挥重要作用。 的 首席研究员建议使用线（他已经开发， 的永生化大鼠近曲小管细胞（IRPTC）的特征）， 断奶大鼠肾脏表达RAS的所有成分，包括 以Ang Ⅱ受体亚型AT 1和AT 2为模型。 研究将集中在 Ang Ⅱ在PT损伤和修复中的作用。 总的假设是， PT损伤涉及PT中AT 1和AT 2的调节;此外， AT 1受体活化导致细胞生长和增殖，而AT 2 抑制生长以及AT 1表达，随后导致程序化细胞 死亡 使用IRPTC氧化损伤模型，提出的具体目标将 测试以下假设：1）PT损伤最初上调 AT 1和AT 2表达; 2）PT损伤诱导内源性Ang释放 II，其影响AT 1和AT 2受体两者的后续转录; 以及3）在修复期间在AT 2和AT 1之间存在串扰，即，的 AT 2受体激活通过细胞内Na+抑制AT 1表达 加载，随后AT 2诱导程序性细胞死亡。

DESCRIPTION (Adapted from the Applicant's Abstract): The renal proximal tubule (PT) plays an important role in homeostasis by reabsorption of salt and water and yet is often exposed to toxic and ischemic insults, and thus constantly undergoes injury and repair. Indeed, PT injury is a major cause of renal failure. PT contains a complete renin-angiotensin system (RAS) and produces endogenous angiotensin II (Ang II). Angiotensin converting enzyme inhibitor effectively slows progression of chronic renal insufficiency, and may ameliorate tubulointerstitial injury. Therefore, the RAS and its product, Ang II, may play an important role in PT injury and repair. The principal investigator proposes to use lines (that he has developed and characterized) of immortalized rat proximal tubule cells (IRPTC) from weanling rat kidney that express all the components of the RAS, including Ang II receptor subtypes AT1 and AT2, as a model. The studies will focus on the role of Ang II in PT injury and repair. The overall hypothesis is that PT injury involves modulation of both AT1 and AT2 in PT; furthermore, that AT1 receptor activation leads to cell growth and proliferation, while AT2 inhibits growth as well as AT1 expression, later leading to programmed cell death. Using an IRPTC oxidant injury model, the Specific Aims proposed will test the following hypotheses: 1) that PT injury initially upregulates both AT1 and AT2 expression; 2) that PT injury induces release of endogenous Ang II which influences subsequent transcription of both AT1 and AT2 receptors; and 3) that during repair there is crosstalk between AT2 and AT1, i.e., that AT2 receptor activation inhibits AT1 expression through intracellular Na+ loading, and later AT2 induces programmed cell death.