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(Hypertension. 2000;35:329.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Obesity Is Associated With Tissue-Specific Activation of Renal Angiotensin-Converting Enzyme In Vivo
Evidence for a Regulatory Role of Endothelin
Presented in part at the Gordon Research Conference on Angiotensin, Queen’s College, Oxford, UK, August 8–13, 1999.
From the Cardiology section, Department of Medicine (M.B., L.V.d’U., T.L., T.F.L.), University Hospital Zürich, and Cardiovascular Research Laboratory (M.B., L.V.d’U., T.L., T.F.L.), Institute of Physiology, University of Zürich, Switzerland; Laboratory of Genetics and Molecular Cardiology (R.C., J.E.K.), Heart Institute, University of São Paolo School of Medicine, São Paulo, Brazil; Institute of Pathophysiology (H.M., W.G.), Faculty of Medicine, Martin-Luther University Halle-Wittenberg, Halle, Germany; Central Laboratory (H.H.), BASF Pharma, Ludwigshafen, Germany; Preclinical Cardiology, Knoll AG, Ludwigshafen (K.M.), Germany; Experimental Pathology (C.C.H.), Jerome H. Holland Laboratory, Rockville, Md; and Department of Clinical Research (S.S.), University of Bern, Switzerland.
Correspondence to Matthias Barton, MD, Division of Cardiology, Department of Medicine, University Hospital, CH-8091 Zürich, Switzerland. E-mail matthiasbarton{at}compuserve.com
Abstract—In the C57BL/6J mice model, we investigated whether obesity affects the function or expression of components of the tissue renin-angiotensin system and whether endothelin (ET)-1 contributes to these changes. ACE activity (nmol · L His-Leu · mg protein-1) was measured in lung, kidney, and liver in control (receiving standard chow) and obese animals treated for 30 weeks with a high-fat, low cholesterol diet alone or in combination with LU135252, an orally active ETA receptor antagonist. ACE mRNA expression was measured in the kidney, and the effects of LU135252 on purified human ACE were determined. Aortic and renal tissue ET-1 protein content was measured, and the vascular contractility to angiotensin II was assessed. Obesity was associated with a tissue-specific increase in ACE activity in the kidney (55±4 versus 33±3 nmol/L) but not in the lung (34±2 versus 32±2 nmol/L). Long-term LU135252 treatment completely prevented this activation (13.3±0.3 versus 55±4 nmol/L, P<0.05) independent of ACE mRNA expression, body weight, or renal ET-1 protein but did not affect pulmonary or hepatic ACE activity. Obesity potentiated contractions in response to angiotensin II in the aorta (from 6±2% to 33±5% KCl) but not in the carotid artery (4±1% to 3.6±1% KCl), an effect that was completely prevented with LU135252 treatment (6±0.4% versus 33±5% KCl). No effect of LU135252 on purified ACE was observed. Thus, obesity is associated with the activation of renal ACE in vivo independent of its mRNA expression and enhanced vascular contractility to angiotensin II. These effects are regulated by ET in an organ-specific manner, providing novel mechanisms by which ET antagonists may exert organ protection.
Key Words: risk factors • aorta • carotid arteries • vasoconstriction • diet • cholesterol • gene expression
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