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Principal Investigator: Elizabeth Gray
Organization: UNIVERSITY OF HOUSTON
Fiscal Year: 2019
Award: $34,186
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Abstract
The increasing world-wide prevalence of obesity is a worrying public health problem and crisis. Coexistence of
obesity, hypertension and diabetes significantly increases the risk of kidney dysfunction. In obesity,
concentrations of angiotensin II (Ang II) increase, while those of Ang-(1-7) decrease along with activity of
angiotensin converting enzyme 2 (ACE2). Neprilysin (NEP) and ACE2 are metallopeptidases that process Ang
I and Ang II, respectively into the Mas receptor agonist, Ang-(1-7). The activity of these protective renin
angiotensin system (RAS) components counterbalances the detrimental biological effects of the classical Ang
II/angiotensin II type 1 receptor (AT1R) RAS axis. Recently published and preliminary data from our laboratory
suggests that treatment with AT2R agonist compound 21 (C21) decreases Ang II and increases Ang-(1-7) in the
kidney of obese Zucker rats, by increasing expression and activity of ACE2. Furthermore, our in vitro data
suggests that AT2R agonist treatment decreases renin activity as well. Entresto, a dual AT1R blocker (valsartan)
and neprilysin inhibitor (sacubitril) recently released to the market was found to be superior to enalapril therapy
alone in the PARADIGM HF trial, resulting in its indication for heart failure with reduced ejection fraction. The
benefits of Entresto are accredited to its ability to increase concentrations of atrial natriuretic peptide (ANP),
another substrate of NEP, while blocking the increasing concentrations of Ang II from acting on AT1R. Yet,
Entresto was found to cause an increase in the urinary albumin/creatinine ratio, an indicator of kidney injury.
This knowledge along with our preliminary results led to our hypothesis that Ang-(1-7) level in obese kidney is
decreased by NEP inhibition, with concurrent increase in Ang II. Combination therapy with C21 increases Ang-
(1-7) and attenuates Ang II, by increasing ACE2 activity and expression. Moreover, C21 with NEP inhibition
produces an additive effect on increasing ANP levels in obese kidney protecting function and structural integrity
of the kidney. To test this hypothesis, Aim 1 is directed to determine the basal levels and basic metabolism of
Ang peptides and ANP in obese kidney. Aim 2 will determine that combined treatment (short-term) with NEP
inhibitor and AT2R agonist enhances ACE2 activity and Ang-(1-7) levels, and attenuates Ang II levels and ANP
degradation in obesity. Aim 3 will determine that chronic combination therapy with a NEP inhibitor and AT2R
agonist is reno-protective in salt-induced hypertension in obesity and is superior to Entresto (ARB + NEP
inhibitor). Female obese Zucker rats are included in aim 3 to investigate the sex specific outcomes of our novel
combinatory approach and to determine if it is equally effective in both male and female obese Zucker rats. To
accomplish these aims, Ang peptides will be quantified utilizing our new liquid chromatography tandem mass
spectrometry method; biochemical, histological and hemodynamic approaches to study renal function/injury and
telemetry for monitoring blood pressure. The proposed work will significantly contribute to understanding Ang
metabolism in obesity and impact future clinical perspectives for a novel reno-protective therapeutic approach.
Terms: <Accreditation><Agonist><Albumins><Albuminuria><AngII><Angiotensin AT1 Receptor><Angiotensin AT2 Receptor><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Angiotensin II Type 1 Receptor><Angiotensin II Type 1 Receptor Antagonists><Angiotensin II Type 1 Receptor Blockers><Angiotensin Receptor 2><Angiotensin-Forming Enzyme><Angiotensinogenase><Atrial Natriuretic Factor><Atrial Natriuretic Peptides><Atriopeptins><Attenuated><Auriculin><Binding><Biochemical><Biological><Blood Plasma><Blood Pressure><Blood Pressure Monitors><CD10 Antigens><CD143 Antigens><Carboxycathepsin><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular Physiology><Cardiovascular system><Chronic><Clinical><Combined Modality Therapy><Common Rat Strains><Comorbidity><Continuous Sphygmomanometers><Creatinine><Data><Diabetes Mellitus><Diet><Dipeptidyl Peptidase A><Drugs><EFRAC><Ejection Fraction><Enacard><Enalapril><Enkephalinase><Female><Future><Glomerular Filtration Rate><Heart Vascular><Heart failure><Histologic><Histologically><Hypertension><Impairment><In Vitro><Incubated><Individual><Injury><Intermediary Metabolism><Kidney><Kidney Urinary System><Kininase A><Kininase II><Knowledge><Laboratories><Leanness><Liquid Chromatography><Mediating><Medication><Membrane Metalloendopeptidase><Messenger RNA><Metabolic Processes><Metabolism><Metallopeptidases><Metalloproteases><Metalloproteinases><Methods><Molecular Interaction><Monitor><Multimodal Therapy><Multimodal Treatment><Na element><Natriuresis><Natriuretic Peptide Hormones><Natriuretic Peptides><Neprilysin><Neutral Endopeptidase><Obesity><Obesity Related Hypertension><Outcome><Pathologic><Pathology><Peptide Metabolism><Peptide Receptor><Peptides><Peptidyl-Dipeptidase A><Periodic Acid Schiff><Periodic acid Schiff stain method><Pharmaceutic Preparations><Pharmaceutical Preparations><Plasma><Plasma Serum><Prevalence><Process><Production><Proteins><Proteinuria><Public Health><Publishing><R-Series Research Projects><R01 Mechanism><R01 Program><Rat><Rats Mammals><Rattus><Receptor Protein><Receptor, Angiotensin, Type 1><Receptor, Angiotensin, Type 2><Renal function><Renin><Renin-Angiotensin System><Renitec><Renitek><Reporting><Research Grants><Research Project Grants><Research Projects><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Site><Sodium><Sodium Chloride><Stable Isotope Labeling><Staining method><Stains><Structure><Suspension substance><Suspensions><Telemetries><Telemetry><Testing><Therapeutic><Thinness><Treatment Period><Type 1 Angiotensin Receptor Antagonists><Type 1 Angiotensin Receptor Blockers><Type 2 Angiotensin II Receptor><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vasodilatation><Vasodilation><Vasorelaxation><Vasotec><Work><Zucker Rats><adiposity><atrial natriuretic hormone><cardiac failure><cardiovascular function><circulatory system><co-morbidity><combination therapy><combined modality treatment><combined treatment><corpulence><corpulency><corpulentia><diabetes><dietary><drug/agent><hemodynamics><high blood pressure><high salt diet><high sodium diet><hyperpiesia><hyperpiesis><hypertensive disease><improved><inhibitor><inhibitor/antagonist><kidney cortex><kidney cortical portion><kidney dysfunction><kidney function><mRNA><male><multi-modal therapy><multi-modal treatment><new approaches><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel strategies><novel strategy><novel therapeutics><novel therapy><obese><obese people><obese person><obese population><obesity treatment><pre-doc><pre-doctoral><predoc><predoctoral><pressure><receptor><receptor expression><renal><renal cortex><renal dysfunction><response><salt><salt hypertension><salt induced hypertension><salt sensitive hypertension><sex><tandem mass spectrometry><treatment days><treatment duration><urinary><valsartan>