Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin–angiotensin system

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• 作者：Maki Uraoka ; Koji Ikeda ; Yusuke Nakagawa ; Masahiro Koide ; Yoshiki Akakabe ; Ritsuko Nakano-Kurimoto ; Tomosaburo Takahashi ; Satoaki Matoba ; Hiroyuki Yamada ; Mitsuhiko Okigaki ; Hiroaki Matsubara
• 关键词：Angiogenesis ; Endothelial cells ; Prorenin ; (Pro)renin receptor
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2009
• 出版时间：25 December 2009
• 年：2009
• 卷：390
• 期：4
• 页码：1202-1207
• 全文大小：472 K

文摘

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.