Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes.
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 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 (AT(1)) receptor antagonists losartan or valsartan; the angiotensin type 2 (AT(2)) 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-Ala(7)]-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.
Gallagher
Patricia E
PE
The Hypertension and Vascular Disease Center, Wake Forest Univ. School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1032, USA. pgallagh@wfubmc.edu
Chappell
Mark C
MC
Ferrario
Carlos M
CM
Tallant
E Ann
EA
D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002268:Carboxypeptidases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D005260:Female; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000378:metabolism; D019808:Losartan / Q000378:metabolism; D008526:Medulla Oblongata / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A; D011247:Pregnancy; D011725:Pyridines / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000378:metabolism; D000068756:Valsartan; D014662:Vasoconstrictor Agents / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; D012333:RNA, Messenger; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; D000068756:Valsartan; D000803:Angiotensin I; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D014633:Valine; C118790:angiotensin I (1-7); D019808:Losartan