doi: 10.1161/hy0202.103002
(Hypertension. 2002;39:573.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Prorenin-Induced Myocyte Proliferation
No Role for Intracellular Angiotensin II
From the Cardiovascular Research Institute COEUR, Departments of Pharmacology (J.J.S., M.M.E.D.v.d.E., P.R.S., A.H.J.D.), Internal Medicine (J.J.S., M.M.E.D.v.d.E., M.A.D.H.S.), and Biochemistry (J.M.J.L.), Erasmus University Medical Center Rotterdam, The Netherlands.
Correspondence to A.H.J. Danser, PhD, Department of Pharmacology, Room EE1418b, Erasmus University Rotterdam, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail danser{at}farma.fgg.eur.nl
Cardiomyocytes bind, internalize, and activate prorenin, the inactive precursor of renin, via a mannose 6-phosphate receptor (M6PR)–dependent mechanism. M6PRs couple directly to G-proteins. To investigate whether prorenin binding to cardiomyocytes elicits a response, and if so, whether this response depends on angiotensin (Ang) II, we incubated neonatal rat cardiomyocytes with 2 nmol/L prorenin and/or 150 nmol/L angiotensinogen, with or without 10 mmol/L M6P, 1 µmol/L eprosartan, or 1 µmol/L PD123319 to block M6P and AT1 and AT2 receptors, respectively. Protein and DNA synthesis were studied by quantifying [3H]-leucine and [3H]-thymidine incorporation. For comparison, studies with 100 nmol/L Ang II were also performed. Neither prorenin alone, nor angiotensinogen alone, affected protein or DNA synthesis. Prorenin plus angiotensinogen increased [3H]-leucine incorporation (+21±5%, mean±SEM, P<0.01), [3H]-thymidine incorporation (+29±6%, P<0.01), and total cellular protein (+14±3%, P<0.01), whereas Ang II increased DNA synthesis only (+34±7%, P<0.01). Eprosartan, but not PD123319 or M6P, blocked the effects of prorenin plus angiotensinogen as well as the effects of Ang II. Medium Ang II levels during prorenin and angiotensinogen incubation were <1 nmol/L. In conclusion, prorenin binding to M6PRs on cardiomyocytes per se does not result in enhanced protein or DNA synthesis. However, through Ang II generation, prorenin is capable of inducing myocyte hypertrophy and proliferation. Because this generation occurs independently of M6PRs, it most likely depends on the catalytic activity of intact prorenin in the medium (because of temporal prosegment unfolding) rather than its intracellular activation. Taken together, our results do not support the concept of Ang II generation in cardiomyocytes following intracellular prorenin activation.
Key Words: myocytes • renin • insulin growth factor • receptors, angiotensin
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