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

Uraoka, Maki; Ikeda, Koji; Nakagawa, Yusuke; Koide, Masaaki; Akakabe, Yoshiki; Nakano-Kurimoto, Ritsuko; Takahashi, Toshifumi; Matoba, Satoaki; Yamada, Hiroyuki; Okigaki, Mitsuhiko; Matsubara, Hiroaki

doi:10.1016/j.bbrc.2009.10.121

Cited by 45 publications

(38 citation statements)

References 27 publications

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“…It has been reported that (pro)renin receptor activation, independent of Ang II, can induce ERK 1/2 phosphorylation in rat and human mesangial cells [2,15], human and rat VSMCs [5,16,19], vascular endothelial cells [21], and U937 monocytes [22]. We found prorenin to stimulate ERK 1/2 phosphorylation, independent of Ang II, in agreement with prior reports [5,15,16,19,22].…”

Section: Discussionsupporting

confidence: 94%

Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway

Liu

Hitomi²,

Hosomi

et al. 2011

Journal of Hypertension

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Section: Discussionsupporting

confidence: 94%

Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway

Liu

Hitomi²,

Hosomi

et al. 2011

Journal of Hypertension

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“…Furthermore, Uraoka et al 18 reported the expression of (P)RR on the membrane of HUVECs that induced ERK activation after binding to prorenin.…”

Section: Huvecs and S(p)rrmentioning

confidence: 99%

Qualitative and quantitative analyses of (pro)renin receptor in the medium of cultured human umbilical vein endothelial cells

et al. 2011

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A 30-kDa protein in the medium of cultured human umbilical vein endothelial cells (HUVECs) was identified as (pro)renin receptor, (P)RR, by western blot analysis using anti-human (P)RR antibodies. The protein bound recombinant human prorenin with a K D of 4.0 nmol l À1 and activated prorenin. These observations suggest the presence of soluble (P)RR, s(P)RR, in the medium of cultured HUVECs. For quantification of the s(P)RR in the medium, an enzyme-linked immunosorbent assay (ELISA) was established. The quantitative range of the ELISA was validated over a nominal range of 7.5-300 pmol l À1 in the wells of a microtiter plate. The assay system showed good linearity (r 2 ¼0.99) with interassay (5.8-9.7%) and intraassay (2.1-7.0%) precision. Using this method, the concentration of s(P)RR in the culture medium of HUVECs was measured to be 32 pmol l À1 . Therefore, these results show qualitative and quantitative evidence that prorenin can be activated after binding to s(P)RR secreted from cultured HUVECs.

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“…The (pro)renin-induced effects on PAI-1 release were additive to those of AngII [113,115]. In neonatal rat cardiomyocytes, 2 nmol/l prorenin-induced p38 MAPK activation resulted in HSP27 (heat-shock protein 27) phosphorylation and an alteration in actin filament dynamics [112], and implanting Matrigel plugs containing 100 nmol/l human prorenin in mouse flanks facilitated neovascularization, possibly because prorenin induced ERK1/2 activation in endothelial cells at such high concentrations [117].…”

Section: Vessel Wall and Heartmentioning

confidence: 90%

(Pro)renin and its receptors: pathophysiological implications

Batenburg

Danser

2012

Clinical Science

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Tissue angiotensin generation depends on the uptake of circulating (kidney-derived) renin and/or its precursor prorenin [together denoted as (pro)renin]. Since tissue renin levels are usually somewhat higher than expected based upon the amount of (renin-containing) blood in tissue, an active uptake mechanism has been proposed. Several candidates have been evaluated in the past three decades, including a renin-binding protein, the mannose 6-phosphate/insulin-like growth factor II receptor and the (pro)renin receptor. Although the latter seemed the most promising, its nanomolar affinity for renin and prorenin is several orders of magnitude above their actual (picomolar) levels in blood, raising doubt on whether (pro)renin-(pro)renin receptor interaction will ever occur in vivo. A wide range of in vitro studies have now demonstrated (pro)renin-receptor-induced effects at nanomolar renin and prorenin concentrations, resulting in a profibrotic phenotype. In addition, beneficial in vivo effects of the putative (pro)renin receptor blocker HRP (handle region peptide) have been observed, particularly in diabetic animal models. Despite these encouraging results, many other studies have reported either no or even contrasting effects of HRP, and (pro)renin-receptor-knockout studies revealed lethal consequences that are (pro)renin-independent, most probably due to the fact that the (pro)renin receptor co-localizes with vacuolar H+-ATPase and possibly determines the stability of this vital enzyme. The present review summarizes all of the recent findings on the (pro)renin receptor and its blockade, and critically compares it with the other candidates that have been proposed to mediate (pro)renin uptake from blood. It ends with the conclusion that the (pro)renin-(pro)renin receptor interaction, if it occurs in vivo, is limited to (pro)renin-synthesizing organs such as the kidney.

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

Cited by 45 publications

References 27 publications

Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway

Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway

Qualitative and quantitative analyses of (pro)renin receptor in the medium of cultured human umbilical vein endothelial cells

(Pro)renin and its receptors: pathophysiological implications

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