Angiotensin‐II mediates ACE2 internalization and degradation through an angiotensin‐II type I receptor‐dependent mechanism (1066.9)

Abstract

ACE2 mediates the conversion of ang‐II to ang‐(1‐7) and by this mechanism prevents the pathological effects related to the activation of rennin‐angiotensin system (RAS). We previously reported that decreased ACE2 expression and activity leads to the development of Ang‐II‐mediated hypertension in mice. The aim of the present study was to characterize the mechanisms involved in ACE2 down‐regulation during neurogenic hypertension. In ACE2‐transfected Neuro‐2A cells, Ang‐II treatment resulted in a significant attenuation of the enzyme activity. Confocal microscopy experiments demonstrated that in presence of ang‐II, ACE2 is internalized and co‐localizes with Rab7, a lysosomal marker. These effects were prevented by the AT1R blocker losartan and the lysosomal inhibitor leupeptin. In contrast, in HEK293T cells, which lack endogenous AT1R, Ang‐II failed to promote ACE2 internalization. This effect was restored after AT1R transfection. Further, ang‐II enhanced ACE2 ubiquitination and decreased the interactions between AT1R and ACE2. In contrast, ACE2 activity was not changed by transfection of AT2R or Mas1R. In vivo, Ang‐II‐mediated hypertension was blunted by chronic infusion of leupeptin in C57Bl/6, but not in ACE2 knockout mice. This is the first demonstration that elevated Ang‐II levels reduce ACE2 expression and activity by stimulation of lysosomal degradation through an AT1R‐dependent mechanism.Grant Funding Source: P20‐RR‐018766, RO1‐HL093178, Howard University