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1 Hypertension & Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
* To whom correspondence should be addressed. E-mail: pgallagh{at}wfubmc.edu.
Angiotensin converting enzyme 2 (ACE2) is a homologue of ACE that preferentially forms angiotensin-(1-7) [Ang-(1-7)] from angiotensin II (Ang II). Incubation of neonatal rat cerebellar or medullary astrocytes with Ang II reduced ACE2 mRNA approximately 60%, suggesting transcriptional regulation of the enzyme. In contrast, Ang II had no effect on ACE mRNA in astrocytes isolated from either brain region, demonstrating a differential regulation of the two enzymes by Ang II. The Ang II-mediated reduction in ACE2 mRNA was blocked by the angiotensin type 1 (AT1) receptor antagonists, losartan or valsartan; the angiotensin type 2 (AT2) antagonist PD123319 was ineffective. The reduction in ACE2 mRNA by Ang II also was associated with a 50% decrease in cerebellar and medullary ACE2 protein which was blocked by losartan. Treatment of medullary astrocytes with Ang-(1-7), the product of ACE2 hydrolysis of Ang II, did not affect ACE2 mRNA; however, Ang-(1-7) prevented the Ang II-mediated reduction in ACE2 mRNA. Addition of [D-Ala7]-Ang-(1-7), a selective AT(1-7) receptor antagonist, blocked the inhibitory actions of Ang-(1-7). These data are the first to demonstrate transcriptional regulation of ACE2 by Ang II and Ang-(1-7). Since ACE2 preferentially converts Ang II to Ang-(1-7), down-regulation of the enzyme by Ang II constitutes a novel positive feed-forward system within the brain that may favor Ang II-mediated neural responses. Further, the modulatory role of Ang-(1-7) on the transcriptional regulation of ACE2 by Ang II suggests a complex interplay between these peptides that is mediated by distinct receptor systems.
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