Abstract
Abnormal regulation of the renin angiotensin system such as enhanced renal AT1R function and reduced ACE2 activity contributes to obesity-related hypertension. Here, we tested whether long-term AT2R activation affects renal function in obesity using lean and obese Zucker rats treated with the AT2R agonist CGP42112A for 2 weeks. This caused blood pressure to decrease by 13 mm Hg, which was associated with increased urinary sodium excretion in the obese rats. Cortical ACE2 expression and activity, the Mas receptor (MasR), and its ligand angiotensin-(1-7) were all increased in CGP-treated obese compared with control rats. Candesartan-induced natriuresis, a measure of AT₁R function, was reduced but cortical AT₁R expression and angiotensin II levels were similar in CGP-treated obese compared with control rats. Renin and AT2R expression in obese rats was not affected by CGP treatment. In HK-2 cells in vitro, CGP treatment caused increased ACE2 activity and MasR levels but decreased AT₁R levels and renin activity. Thus, long-term AT2R activation shifts the opposing arms of renin angiotensin system and contributes to natriuresis and blood pressure reduction in obese animals. Our study highlights the importance of AT2R as a target for treating obesity-related hypertension.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Angiotensin I / metabolism
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Angiotensin II Type 1 Receptor Blockers / pharmacology
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Angiotensin-Converting Enzyme 2
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Animals
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Antihypertensive Agents / pharmacology*
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Blood Pressure*
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Cell Line
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Disease Models, Animal
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Glomerular Filtration Rate / drug effects
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Humans
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Hypertension / enzymology
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Hypertension / etiology
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Hypertension / genetics
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Hypertension / physiopathology
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Hypertension / prevention & control*
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Kidney Cortex / drug effects*
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Kidney Cortex / enzymology
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Kidney Cortex / physiopathology
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Male
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Natriuresis / drug effects
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Obesity / complications
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Obesity / drug therapy*
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Obesity / enzymology
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Obesity / genetics
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Obesity / physiopathology
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Oligopeptides / pharmacology*
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Peptide Fragments / metabolism
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Peptidyl-Dipeptidase A / metabolism*
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Proto-Oncogene Mas
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Proto-Oncogene Proteins / metabolism
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Rats
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Rats, Zucker
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Receptor, Angiotensin, Type 1 / metabolism*
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Receptor, Angiotensin, Type 2 / agonists*
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Receptor, Angiotensin, Type 2 / metabolism
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Receptors, G-Protein-Coupled / metabolism
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Renin / metabolism
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Renin-Angiotensin System / drug effects*
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Time Factors
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Up-Regulation
Substances
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Angiotensin II Type 1 Receptor Blockers
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Antihypertensive Agents
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MAS1 protein, human
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Oligopeptides
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Peptide Fragments
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Receptors, G-Protein-Coupled
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CGP 42112A
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Angiotensin I
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Peptidyl-Dipeptidase A
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ACE2 protein, human
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Ace2 protein, rat
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Angiotensin-Converting Enzyme 2
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Renin
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angiotensin I (1-7)