TY  - GEN
N2  - Angiotensin 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.
DO  - 10.6083/bpxhc42698
DO  - doi
AB  - Angiotensin 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.
AD  - Oregon Health and Science University
T1  - Integrated physiological effects of ACE2 in the cardiovascular system
ED  - Gurley, Susan
ED  - Hutchens, Michael
ED  - Mentor
ED  - Co-Mentor
DA  - 2024-02-14
AU  - Emathinger, Jacqueline
L1  - https://digitalcollections.ohsu.edu/record/42698/files/Emathinger.Jacqueline.2024.pdf
PB  - Oregon Health and Science University
LA  - eng
PY  - 2024-02-14
ID  - 42698
L4  - https://digitalcollections.ohsu.edu/record/42698/files/Emathinger.Jacqueline.2024.pdf
KW  - Renin-Angiotensin System
KW  - Angiotensin-Converting Enzyme 2
KW  - Hypertension
KW  - Acute Kidney Injury
KW  - Cardiovascular System
KW  - Epithelial Sodium Channels
KW  - Mice, Transgenic
KW  - renin-angiotensin system
KW  - ACE2
KW  - hypertension
KW  - acute kidney injury
KW  - cardiovascular physiology
TI  - Integrated physiological effects of ACE2 in the cardiovascular system
Y1  - 2024-02-14
L2  - https://digitalcollections.ohsu.edu/record/42698/files/Emathinger.Jacqueline.2024.pdf
LK  - https://digitalcollections.ohsu.edu/record/42698/files/Emathinger.Jacqueline.2024.pdf
UR  - https://digitalcollections.ohsu.edu/record/42698/files/Emathinger.Jacqueline.2024.pdf
ER  -