Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin-angiotensin system.
Prorenin is an enzymatically inactive precursor of renin, and its biological function in endothelial cells (ECs) is unknown despite its relevance with the incidence of diabetic microvascular complications. Recently, (pro)renin receptor was identified, and the receptor-associated prorenin system has been discovered, whereas its expression as well as function in ECs remain unclear. In the present study, we found that ECs express the (pro)renin receptor, and that prorenin provoked ERK activation through (pro)renin receptor independently of the renin-angiotensin system (RAS). Prorenin stimulated the proliferation, migration and tube-formation of ECs, while it inhibited endothelial apoptosis induced by serum and growth factor depletion. MEK inhibitor abrogated these proangiogenic effects of prorenin, while AT1 receptor antagonist or angiotensin-converting enzyme inhibitor failed to block them. In vivo neovascularization in the Matrigel-plugs implanted into mouse flanks was significantly enhanced by prorenin, in which significant ERK activation was detected in ECs. Furthermore, tumor xenografts stably transfected with prorenin demonstrated the significantly accelerated growth rate concomitantly with enhanced intratumoral neovascularization. Our data demonstrated that the RAS-independent (pro)renin receptor-mediated signal transduction plays a pivotal role in the regulation of ECs function as well as in the neovascularization, and thus prorenin is potentially involved in the pathophysiology of diabetic microvascular complications as well as cancers.
Uraoka
Maki
M
Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566, Japan.
Ikeda
Koji
K
Nakagawa
Yusuke
Y
Koide
Masahiro
M
Akakabe
Yoshiki
Y
Nakano-Kurimoto
Ritsuko
R
Takahashi
Tomosaburo
T
Matoba
Satoaki
S
Yamada
Hiroyuki
H
Okigaki
Mitsuhiko
M
Matsubara
Hiroaki
H
D000818:Animals; D002465:Cell Movement; D004730:Endothelium, Vascular / Q000201:enzymology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000502:physiology*; D012083:Renin / Q000235:genetics / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000502:physiology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000093342:Prorenin Receptor
D011956:Receptors, Cell Surface; D048049:Extracellular Signal-Regulated MAP Kinases; D012083:Renin; D000093342:Prorenin Receptor