ANGIOTENSIN RECEPTOR TOPOLOGY AND FUNCTION

血管紧张素受体的拓扑结构和功能

• 批准号: 2701199
• 负责人: SHIOW-SHIH TANG
• 金额: $ 22.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2701199
• 关键词: angiotensins; apoptosis; autocrine; gene induction /repression; hormone receptor; hormone regulation /control mechanism; kidney disorder; laboratory rat; protein isoforms; protein structure function; receptor expression; renal tubule; sodium ion; tissue /cell culture

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.

描述(摘自申请者的摘要)：肾脏近端 小管(PT)在盐分重吸收的动态平衡中起着重要作用 和水，但经常暴露在有毒和缺血的侮辱中，因此 不断地经历受伤和修复。事实上，PT损伤是一个主要原因 肾功能衰竭的症状。PT含有完整的肾素-血管紧张素系统(RAS)和 产生内源性血管紧张素II(Ang II)。血管紧张素转换酶 抑制物有效延缓慢性肾功能不全的进展， 可改善肾小管间质损伤。因此，RAS及其 Ang II产物可能在PT损伤修复中发挥重要作用。这个 首席调查员建议使用(他开发和开发的)线路 永生化大鼠近端小管细胞(IRPTC)的特征 表达RAS的所有成分的断奶大鼠肾脏，包括 Ang II受体亚型AT1和AT2，作为模型。这些研究将集中在 血管紧张素Ⅱ在甲状旁腺损伤修复中的作用总体假设是 PT损伤涉及PT中AT1和AT2的调节；此外， AT1受体激活导致细胞生长和增殖，而AT2受体激活导致细胞生长和增殖 抑制生长和AT1的表达，后来导致编程细胞 死亡。使用IRPTC氧化剂损伤模型，提出的具体目标将 检验以下假设：1)甲状旁腺皮质损伤最初上调两者 AT1和AT2的表达；2)PT损伤诱导内源性Ang的释放 II影响AT1和AT2受体的后续转录； 以及3)在修复期间，AT2和AT1之间存在串扰，即 AT2受体激活通过细胞内Na+抑制AT1的表达 加载，以及后来的AT2诱导细胞程序性死亡。