Distinct roles for ANG II and ANG-(1–7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes

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Abstract
Angiotensin-converting enzyme 2 (ACE2) is a homolog 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 by ∼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. The 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). Because ACE2 preferentially converts ANG II to ANG-(1–7), downregulation of the enzyme by ANG II constitutes a novel positive feed-forward system within the brain that may favor ANG II-mediated neural responses. Furthermore, the modulatory role of ANG-(1–7) in the transcriptional regulation of ACE2 by ANG II suggests a complex interplay between these peptides that is mediated by distinct receptor systems.