Obesity is associated with tissue-specific activation of renal angiotensin-converting enzyme in vivo: evidence for a regulatory role of endothelin.
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 ET(A) 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.
Barton
M
M
Cardiology Section, Department of Medicine, University Hospital Zürich, and Cardiovascular Research Laborator, Institute of Physiology, University of Zürich, Switzerland.matthiasbarton@compuser ve.com
Carmona
R
R
Morawietz
H
H
d'Uscio
L V
LV
Goettsch
W
W
Hillen
H
H
Haudenschild
C C
CC
Krieger
J E
JE
Münter
K
K
Lattmann
T
T
Lüscher
T F
TF
Shaw
S
S
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D002784:Cholesterol / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004032:Diet; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000032:analysis / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000201:enzymology*; D009924:Organ Culture Techniques; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism*; D010666:Phenylpropionates / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D044022:Receptor, Endothelin A; D012084:Renin-Angiotensin System / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D014662:Vasoconstrictor Agents; C054215:SQ 30741; D000804:Angiotensin II; C107831:darusentan; D013928:Thromboxane A2; D002784:Cholesterol; D007703:Peptidyl-Dipeptidase A; D007213:Indomethacin