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Principal Investigator: Susan Bailey Gurley
Organization: UNIVERSITY OF SOUTHERN CALIFORNIA
Fiscal Year: 2024
Award: $540,092
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Acute Renal Failure with Renal Papillary Necrosis><Address><Affect><Affinity><AngII><Angiotensin AT1 Receptor><Angiotensin II><Angiotensin II Type 1 Receptor><Animal Model><Animal Models and Related Studies><Attenuated><Autoregulation><BP control><BP homeostasis><BP management><BP reduction><BP regulation><Blood><Blood Pressure><Blood Reticuloendothelial System><Blood Serum><Blood Vessels><Body Tissues><Brush Border><COVID complications><COVID related complications><COVID-19><COVID-19 complications><COVID-19 related complications><COVID-19 virus><COVID19 virus><CV-19><Cardiovascular Diseases><Cell Body><Cells><CoV-2><CoV2><Coronavirus Infectious Disease 2019><Coupled><Data><Development><Disease><Disorder><Endothelial Cells><Equilibrium><Excretory function><Female><Filtration><Filtration Fractionation><Gene Targeting><Goals><Homeostasis><Hypertension><Infusion><Infusion procedures><KO mice><Kidney><Kidney Urinary System><Knock-out Mice><Knockout Mice><Knowledge><Length><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Membrane><Metallopeptidases><Metalloproteases><Metalloproteinases><Mice><Mice Mammals><Micropuncture><Modeling><Molecular><Murine><Mus><Mutate><Natriuresis><Nephrons><Null Mouse><Pathogenesis><Pathway interactions><Patients><Peptides><Persons><Phase><Phenotype><Physiologic><Physiological><Physiological Homeostasis><Play><Predisposition><Proximal Kidney Tubules><Receptor Protein><Receptor, Angiotensin, Type 1><Renal function><Renin-Angiotensin System><Resistance><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Source><Striated Border><Susceptibility><Techniques><Testing><Tissues><Transplantation><Tubular><Tubular formation><Urine><Uriniferous Tube><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Virus><Work><Wuhan coronavirus><acute kidney injury><angiotensin II type I receptor><angiotensin converting enzyme 2><angiotensin converting enzyme II><attenuate><attenuates><balance><balance function><blood pressure control><blood pressure elevation><blood pressure homeostasis><blood pressure management><blood pressure reduction><blood pressure regulation><cardiovascular disorder><cell type><complications due to COVID-19><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><defined contribution><developmental><elevated blood pressure><excretion><experiment><experimental research><experimental study><experiments><glomerular filtration><hCoV19><high blood pressure><hyperpiesia><hyperpiesis><hypertension treatment><hypertensive><hypertensive disease><hypertensive disorder><improved><increase in blood pressure><increased blood pressure><infusions><kidney function><lower BP><lower blood pressure><lowers blood pressure><male><member><membrane structure><model of animal><multi-photon><nCoV2><nano meter scale><nano meter sized><nanometer scale><nanometer sized><nanoscale><novel><pathway><receptor><reduce BP><reduce blood pressure><reduction in BP><reduction in blood pressure><regulate BP><regulate blood pressure><renal><renal proximal tubule><resistant><social role><solute><transplant><urinary><vascular>