Role of Nonproteolytically Activated Prorenin in Pathologic, but Not Physiologic, Retinal Neovascularization

Satofuka, Shingo; Ichihara, Atsuhiro; Nagai, Norihiro; Koto, Takashi; Shinoda, Hajime; Noda, Kousuke; Ozawa, Yoko; Inoue, Makoto; Tsubota, Kazuo; Itoh, Hiroshi; Oike, Yuichi; Ishida, Susumu

doi:10.1167/iovs.06-0534

Cited by 72 publications

(97 citation statements)

References 48 publications

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“…1d-f, f″) and in Müller cells within the inner nuclear layer (Fig. 1d-f), which is consistent with previous reports [14,17,29]. Antibody Ms3-24 also detected a signal in the photoreceptor layer (Fig.…”

Section: Resultssupporting

confidence: 92%

“…7). These novel findings on human samples, in concert with our previous data using rodent models [17,18], further support the pathogenic role of (P)RR in the development of PDR, which is characterised by VEGFdriven angiogenesis.…”

Section: Discussionsupporting

confidence: 84%

“…In this study, we investigated localisation and expression of (P)RR in fibrovascular tissues and vitreous fluids from patients with PDR and evaluated the molecular mechanisms in vitro to confirm ideas about (P)RR from previous animal studies [14,[17][18][19][20][21]. We herein report the first evidence of a close association between (P)RR and angiogenic activity in human PDR.…”

Section: Introductionmentioning

confidence: 56%

“…Endothelial localisation of (P)RR in human PDR fibrovascular tissues (P)RR localisation to retinal vessels was previously demonstrated in rodents [14,17,19,29]; however, no studies on human ocular tissue have been reported. First, we confirmed mRNA expression of (P)RR and RAS compo- (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Prorenin binding to (P)RR activates RAS-independent signal transduction via mitogenactivated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) 1/2 and p38, both of which contribute to the pathogenesis of organ damage [15,16]. The dual activation of tissue RAS and RAS-independent signalling pathways, referred to as the receptor-associated prorenin system (RAPS), has been shown to be involved in the molecular pathogenesis of retinal vascular disorders such as inflammation and angiogenesis [14,[17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

et al. 2012

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Aims/hypothesis The renin-angiotensin system (RAS) potentially has a role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor for diabetic retinopathy. We have recently shown significant involvement of (pro)renin receptor ([P]RR) in retinal inflammation in a rodent model of early diabetes. In this study we aim to elucidate the (P)RR-associated pathogenesis of fibrovascular proliferation, a late-stage angiogenic complication in human diabetic retinopathy. Methods Vitreous fluids from 23 eyes of patients with proliferative diabetic retinopathy (PDR) and 16 eyes of controls with non-diabetic, idiopathic macular diseases (macular hole and epiretinal membrane) were collected. Protein levels of soluble (P)RR were measured by ELISA, and immunofluorescence was performed to assess the localisation of (P)RR and related molecules in fibrovascular tissues from PDR eyes. Results (P)RR immunoreactivity was detected in neovascular endothelial cells, colocalised with prorenin, phosphorylated extracellular signal-regulated kinase (ERK) and vascular endothelial growth factor (VEGF). Prorenin application to human retinal microvascular endothelial cells significantly upregulated mRNA expression of VEGF, especially the VEGF165 isoform, which was abolished by (P)RR or ERK signalling blockade. Proteases known to cleave (P)RR, including furin, were positive in endothelial cells in fibrovascular tissues. Protein levels of soluble (P)RR in vitreous fluids were higher in PDR eyes than in non-diabetic control eyes, and correlated significantly with vitreous prorenin and VEGF levels and the vascular density of fibrovascular tissues. Conclusions/interpretation Our data using human samples provide the first evidence that (P)RR is associated with angiogenic activity in PDR.

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

et al. 2012

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The significance of neuronal and glial cell changes in the rat retina during oxygen-induced retinopathy

et al. 2009

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Retinopathy of prematurity is a devastating vascular disease of premature infants. A number of studies indicate that retinal function is affected in this disease. Using the rat model of oxygen-induced retinopathy, it is possible to explore more fully the complex relationship between neuronal, glial and vascular pathology in this condition. This review examines the structural and functional changes that occur in the rat retina following oxygen-induced retinopathy. We highlight that vascular pathology in rats is characterized by aberrant growth of blood vessels into the vitreous at the expense of blood vessel growth into the body of the retina. Moreover, amino acid neurochemistry, a tool for examining neuronal changes in a spatially complete manner reveals widespread changes in amacrine and bipolar cells. In addition, neurochemical anomalies within inner retinal neurons are highly correlated with the absence of retinal vessels. The key cell types that link blood flow with neuronal function are macroglia. Macroglia cells, which in the retina include astrocytes and Müller cells, are affected by oxygen-induced retinopathy. Astrocyte loss occurs in the peripheral retina, while Müller cells show signs of reactive gliosis that is highly localized to regions that are devoid of intraretinal blood vessels. Finally, we propose that treatments, such as blockade of the renin-angiotensin system, that not only targets pathological angiogenesis, but that also promotes re-vascularization of the retina are likely to prove important in the treatment of those with retinopathy of prematurity.

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Glaucoma and the ocular renin-angiotensin-aldosterone system: Update on molecular signalling and treatment perspectives

Buonfiglio,

Pfeiffer,

Gericke

2024

Cellular Signalling

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Role of Nonproteolytically Activated Prorenin in Pathologic, but Not Physiologic, Retinal Neovascularization

Abstract: The present findings suggest that nonproteolytic activation of prorenin selectively promotes pathologic, but not physiologic, retinal neovascularization through the inflammatory processes related to pathologic neovascularization.

Cited by 72 publications

References 48 publications

(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

The significance of neuronal and glial cell changes in the rat retina during oxygen-induced retinopathy

Glaucoma and the ocular renin-angiotensin-aldosterone system: Update on molecular signalling and treatment perspectives

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