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

Abstract

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.

The vitreous renin–angiotensin system is mediated by soluble (pro)renin receptor in diabetic retinopathy: A new implication of the receptor-associated prorenin system

“…24 We recently have shown that s(P)RR, prorenin, activated prorenin, VEGF, and renin activity levels in vitreous fluids were significantly higher in PDR eyes than in nondiabetic control eyes. 25,26 Increased s(P)RR levels in PDR eyes, released from neovascular endothelial cells in fibrovascular tissues, were significantly correlated with vitreous prorenin, activated prorenin, and VEGF levels and the vascular density of fibrovascular tissues. 25 Interestingly, renin activity levels also significantly correlated with the vitreous levels of s(P)RR, prorenin, activated prorenin, and VEGF.…”

“…25,26 Increased s(P)RR levels in PDR eyes, released from neovascular endothelial cells in fibrovascular tissues, were significantly correlated with vitreous prorenin, activated prorenin, and VEGF levels and the vascular density of fibrovascular tissues. 25 Interestingly, renin activity levels also significantly correlated with the vitreous levels of s(P)RR, prorenin, activated prorenin, and VEGF. 26 These data indicate that the vitreous renin activity stems from s(P)RR-mediated nonproteolytic activation of prorenin and the significant role of (P)RR in the pathogenesis of PDR.…”

“…27e30 Furthermore, a close link between the vitreous renin activity and VEGF levels validates our concept of "vitreous RAS" that contributes to the angiogenic activity of DR. Consequently, in concert with vitreous RAS due to s(P)RR (Fig. 1A), 26 retinal RAPS due to membrane-type (i.e., full-length) (P)RR 25 (Fig. 1B) is thought to regulate VEGF expression in DR.…”

“…26 These data indicate that the vitreous renin activity stems from s(P)RR-mediated nonproteolytic activation of prorenin and the significant role of (P)RR in the pathogenesis of PDR. Indeed, (P)RR and RAS components were expressed in diabetic fibrovascular tissues and human retinal cell lines, 25 and the vitreous levels of prorenin and angiotensin II were shown to be elevated in PDR eyes. 27e30 Furthermore, a close link between the vitreous renin activity and VEGF levels validates our concept of "vitreous RAS" that contributes to the angiogenic activity of DR. Consequently, in concert with vitreous RAS due to s(P)RR (Fig.…”

“…Cleavage enzymes for processing full-length (P)RR to s(P)RR include the proprotein convertase furin 31 and ADAM19 (a disintegrin and metalloproteinase), 32 both of which proved to be present in endothelial cells in the fibrovascular tissues in PDR. 25 Gene expression and enzymatic activity of these proteases in the neovascular endothelial cells are likely to define the contribution ratio between vitreous RAS and retinal RAPS. Investigation into the biochemical regulation of furin and ADAM19 is required in the future to further elucidate (P)RR-related molecular pathogenesis of DR.…”