Actions of ACE2 along with Nephron to Regulate Blood Pressure

项目摘要 在美国，高血压影响着超过6000万人，尽管其原因多种多样， 阻断肾素-血管紧张素系统（RAS）可降低大多数人的血压， 高血压患者。ACE 2是RAS的最新成员，我们以前的工作已经 确定ACE 2通过在肾脏代谢中起作用来防止高血压 血管紧张素II，从而调节RAS。作为我们了解如何在全球范围内 RAS影响BP，我们采用了细胞特异性基因靶向和肾脏交叉， 在小鼠中移植以鉴定用于BP调节的ACE 2的关键细胞来源。我们发现 小鼠缺乏特异性来自近端小管的ACE 2（PTACE 2KO）， 肾脏中ACE 2表达最高，在早期阶段血压升高过度， 血管紧张素II型高血压，与血管紧张素II肽的增加积累有关， 肾脏和肾脏sACE 2的尿排泄减少50%。基于肾脏交叉- 在移植实验中，高血压的发展与显著的 血清和尿液中sACE 2的降低，而sACE 2似乎使血压正常化， 缺乏肾脏表达的小鼠。因此，我们的研究结果表明ACE 2起源于PT的 肾脏在血管紧张素II依赖性高血压的起始中起关键作用， 和全身组织都对尿中的sACE 2有贡献。我们的新数据扩大了对 ACE 2如何影响RAS和BP。该修订提案旨在定义分子 导致PTACE 2KO小鼠高血压的机制;确定 肾外ACE 2和脱落对血压调节和血管功能的影响; 并描述了ACE 2到达肾单位内腔以平衡肾单位的机制。 RAS。我们预计我们的研究将改变现有的关于ACE 2功能的范式， 调节血压和中度肾功能，与ACE 2 失调

Project Summary Hypertension affects more than 60 million people in the US and despite its diverse causes, blockade of the renin-angiotensin system (RAS) lowers blood pressure in the majority of hypertensive patients. ACE2 is the newest member of the RAS, and our previous work has established that ACE2 protects against hypertension with actions in the kidney to metabolize angiotensin II, thus regulating the RAS. As part of our overall goal of understanding how the RAS impacts BP, we have employed cell-specific gene-targeting and kidney cross- transplantation in mice to identify the key cellular sources of ACE2 for BP regulation. We found that mice lacking ACE2 specifically from the proximal tubule (PTACE2KO), the cell type with highest expression of ACE2 in the kidney, have exaggerated BP elevation in the early phase of angiotensin II hypertension, associated with enhanced accumulation of angiotensin II peptide in kidney and ≈50% reduction in urinary excretion of sACE2. Based on kidney cross- transplantation experiments, the development of hypertension was associated with significant reductions in sACE2 in both serum and urine whereas sACE2 appeared to normalize BP in mice lacking renal expression. Thus, our findings suggest ACE2 originating from the PT of the kidney plays a key role in the initiation of angiotensin II-dependent hypertension, and that kidney and systemic tissues both contribute to sACE2 in urine. Our new data expand knowledge of how ACE2 can impact the RAS and BP. This revised proposal aims to define molecular mechanisms contributing to hypertension in PTACE2KO mice; establish relative contribution of extra-renal ACE2 and shedding to BP regulation and vascular function with new animal models; and delineate mechanism by which ACE2 reaches the lumen of the nephron to balance the RAS. We anticipate our studies will shift the existing paradigm around how ACE2 functions to regulate BP and moderate kidney function with high relevance to disease states where ACE2 is dysregulated.