000042698 001__ 42698 000042698 005__ 20241219154904.0 000042698 0247_ $$2doi$$a10.6083/bpxhc42698 000042698 037__ $$aETD 000042698 041__ $$aeng 000042698 245__ $$aIntegrated physiological effects of ACE2 in the cardiovascular system 000042698 260__ $$bOregon Health and Science University 000042698 269__ $$a2024-02-14 000042698 336__ $$aDissertation 000042698 502__ $$bPh.D. 000042698 502__ $$gPhysiology & Pharmacology (sunsetting) 000042698 520__ $$aAngiotensin converting enzyme 2 (ACE2) is a key regulator of the renin angiotensin system (RAS) that acts by degrading angiotensin II (AngII). Within the kidney, ACE2 is highly expressed in the proximal tubule (PT), where it is poised to counterbalance the actions of AngII which include regulation of blood pressure and solute balance. Previous studies using knockout or transgenic mice have demonstrated the physiological importance of RAS components including ACE2 in cardiovascular and renal diseases. This dissertation investigates the role of ACE2 in the pathophysiology of two common clinical disorders: hypertension and acute kidney injury. Using a novel transgenic model of PT ACE2 deletion, we investigate the hypothesis that PT-derived ACE2 mitigates the hypertensive response to AngII through regulation of the intrarenal RAS and renal sodium handling. We establish a critical role for ACE2 in the PT in blood pressure regulation via the intrarenal RAS and demonstrate that ACE2 is integral for preservation of the pressure natriuretic response to AngII. Moreover, we show that loss of ACE2 from the PT alters the transcriptional profile of the kidney, reflecting disruption of structural and functional brush border gene expression. This dissertation also delves into the less-explored territory of the contributions of ACE2 in acute kidney injury and recovery. Novel application of an existing humanized ACE2 mouse line in a model of ischemia-reperfusion injury suggests that ACE2 overexpression supports PT brush border resistance to ischemic injury. Studies in mice with selective loss or overexpression of ACE2 provide a platform for dissecting the physiological roles of this enzyme in the kidney. Collectively, the research presented here suggests a fundamental role for ACE2 in cardiovascular and renal physiology. 000042698 536__ $$oAmerican Heart Association $$cPredoctoral Fellowship 916639 000042698 536__ $$oAmerican Society of Nephrology $$cPredoctoral Fellowship 000042698 536__ $$oNational Institute of General Medical Sciences$$c5T32GM109835-03 000042698 536__ $$oDepartment of Health and Human Services$$c5TL1TR002371-05 000042698 540__ $$fCC BY-NC-ND 000042698 542__ $$fIn copyright - single owner 000042698 650__ $$aRenin-Angiotensin System$$025316 000042698 650__ $$aAngiotensin-Converting Enzyme 2$$013488 000042698 650__ $$aHypertension$$020538 000042698 650__ $$aAcute Kidney Injury$$039113 000042698 650__ $$aCardiovascular System$$016153 000042698 650__ $$aEpithelial Sodium Channels$$037426 000042698 650__ $$aMice, Transgenic$$022253 000042698 6531_ $$arenin-angiotensin system 000042698 6531_ $$aACE2 000042698 6531_ $$ahypertension 000042698 6531_ $$aacute kidney injury 000042698 6531_ $$acardiovascular physiology 000042698 691__ $$aSchool of Medicine$$041369 000042698 692__ $$aDepartment of Physiology and Pharmacology$$041442 000042698 7001_ $$aEmathinger, Jacqueline$$uOregon Health and Science University$$041354$$10000-0002-6362-1133 000042698 7201_ $$aGurley, Susan$$uOregon Health and Science University$$041354$$10000 0002 2659 6485$$eMentor$$7Personal 000042698 7201_ $$aHutchens, Michael$$uOregon Health and Science University$$041354$$10000-0001-8583-1812$$eCo-Mentor$$7Personal 000042698 789__ $$eHas part$$w10.1016/j.mce.2021.111255$$2DOI 000042698 792__ $$aEmathinger, J. M., Nelson, J. W. & Gurley, S. B. Advances in use of mouse models to study the renin-angiotensin system. Mol Cell Endocrinol 529, 111255 (2021). 000042698 8564_ $$971b82041-36d0-4b01-aef9-dca90a15b1fb$$s12991614$$uhttps://digitalcollections.ohsu.edu/record/42698/files/Emathinger.Jacqueline.2024.pdf 000042698 909CO $$ooai:digitalcollections.ohsu.edu:42698$$pstudent-work 000042698 980__ $$aTheses and Dissertations 000042698 981__ $$aPublished$$b2024-02-23