Actions of ACE2 along with Nephron to Regulate Blood Pressure

ACE2 与肾单位一起调节血压的作用

• 批准号: 10443478
• 负责人: Susan Bailey Gurley
• 金额: $ 45.62万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443478
• 关键词: 2019-nCoV; ACE2; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Affinity; Angiotensin II; Animal Model; Attenuated; Blood; Blood Pressure; Blood Vessels; Brush Border; COVID-19; COVID-19 complications; Carboxypeptidase; Cardiovascular Diseases; Cells; Coupled; Data; Development; Disease; Endothelial Cells; Equilibrium; Excretory function; Female; Filtration; Gene Targeting; Goals; Homeostasis; Hypertension; Infusion procedures; Kidney; Knockout Mice; Knowledge; Length; Mass Spectrum Analysis; Membrane; Metalloproteases; Micropuncture; Modeling; Molecular; Mus; Mutate; Natriuresis; Nephrons; Pathogenesis; Pathway interactions; Patients; Peptides; Persons; Phase; Phenotype; Physiological; Play; Predisposition; Proximal Kidney Tubules; Receptor, Angiotensin, Type 1; Renal function; Renin-Angiotensin System; Resistance; Role; Sampling; Serum; Source; Techniques; Testing; Tissues; Transplantation; Tubular formation; Urine; Virus; Work; base; blood pressure control; blood pressure elevation; blood pressure reduction; blood pressure regulation; cell type; defined contribution; experimental study; glomerular filtration; hypertension treatment; hypertensive; improved; male; member; nanoscale; novel; receptor; solute; urinary

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.

项目摘要 在美国，高血压影响着6000多万人，尽管其原因多种多样， 阻断肾素-血管紧张素系统(RAS)可降低大多数患者的血压 高血压患者。ACE2是RAS的最新成员，我们以前的工作已经 证实血管紧张素转换酶2通过肾脏新陈代谢来预防高血压 血管紧张素II，从而调节RAS。作为我们总体目标的一部分，我们了解 RAS影响血压，我们采用了细胞特异性基因打靶和肾脏交叉定位。 小鼠移植以确定ACE2调节血压的关键细胞来源。我们发现 缺乏来自近端小管的ACE2的小鼠(PTACE2KO)，具有 血管紧张素转换酶2在肾脏的高表达，在高血压早期加重了血压升高。 血管紧张素II高血压与血管紧张素II肽积聚增加相关 肾脏和≈的尿中sACE2排泄量减少50%。基于肾交叉- 移植实验中，高血压的发展与显著相关 血清和尿液中sACE2的减少，而sACE2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，ACE2起源于 肾脏在血管紧张素II依赖性高血压的发病中起着关键作用，而肾脏 和全身组织都对尿中的sACE2有贡献。我们的新数据扩展了对 ACE2如何影响RAS和BP。这项修订后的提案旨在定义分子 PTACE2KO小鼠高血压发病机制的研究 肾外血管紧张素转换酶2和脱落调节血压和血管功能的新动物模型； 并描述了ACE2到达肾单位管腔以平衡 拉斯。我们预计，我们的研究将围绕ACE2如何发挥作用来改变现有的范式 调节血压，适度肾功能，与ACE2所在的疾病状态高度相关 监管不力。