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 fun ction or expression of components of the tissue renin-angiotensin system an d whether endothelin (ET)-1 contributes to these changes. ACE activity (nmo l.L His-Leu.mg protein(-1)) was measured in lung, kidney, and liver in cont rol (receiving standard chow) and obese animals treated for 30 weeks with a high-fat, low cholesterol diet alone or in combination with LU135252, an o rally active ETA receptor antagonist. ACE mRNA expression was measured in t he kidney, and the effects of LU135252 on purified human ACE were determine d. Aortic and renal tissue ET-1 protein content was measured, and the vascu lar contractility to angiotensin II was assessed. Obesity was associated wi th a tissue-specific increase in ACE activity in the kidney (55 +/- 4 versu s 33 +/- 3 nmol/L) but not in the lung (34 +/- 2 versus 32 +/- 2 nmol/L). L ong-term LU135252 treatment completely prevented this activation (13.3 +/- 0.3 versus 55 +/- 4 nmol/L, P<0.05) independent of ACE mRNA expression, bod y 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 L U135252 treatment (6 +/- 0.4% versus 33 +/- 5% KCl). No effect of LU135252 on purified ACE was observed. Thus, obesity is associated with the activati on of renal ACE in vivo independent of its mRNA expression and enhanced vas cular contractility to angiotensin II. These effects are regulated by ET in an organ-specific manner, providing novel mechanisms by which ET antagonis ts may exert organ protection.