(Pro)renin Receptor–Mediated Signal Transduction and Tissue Renin-Angiotensin System Contribute to Diabetes-Induced Retinal Inflammation

Abstract

OBJECTIVEThe term “receptor-associated prorenin system” (RAPS) refers to the pathogenic mechanisms whereby prorenin binding to its receptor dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor. The aim of the present study was to define the association of the RAPS with diabetes-induced retinal inflammation.RESEARCH DESIGN AND METHODSLong-Evans rats, C57BL/6 mice, and angiotensin II type 1 receptor (AT1-R)-deficient mice with streptozotocin-induced diabetes were treated with (pro)renin receptor blocker (PRRB). Retinal mRNA expression of prorenin and the (pro)renin receptor was examined by quantitative RT-PCR. Leukocyte adhesion to the retinal vasculature was evaluated with a concanavalin A lectin perfusion–labeling technique. Retinal protein levels of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1 were examined by ELISA. Retinal extracellular signal–regulated kinase (ERK) activation was analyzed by Western blotting.RESULTSInduction of diabetes led to significant increase in retinal expression of prorenin but not the (pro)renin receptor. Retinal adherent leukocytes were significantly suppressed with PRRB. Administration of PRRB inhibited diabetes-induced retinal expression of VEGF and ICAM-1. To clarify the role of signal transduction via the (pro)renin receptor in the diabetic retina, we used AT1-R–deficient mice in which the RAS was deactivated. Retinal adherent leukocytes in AT1-R–deficient diabetic mice were significantly suppressed with PRRB. PRRB suppressed the activation of ERK and the production of VEGF, but not ICAM-1, in AT1-R–deficient diabetic mice.CONCLUSIONSThese results indicate a significant contribution of the RAPS to the pathogenesis of diabetes-induced retinal inflammation, suggesting the possibility of the (pro)renin receptor as a novel molecular target for the treatment of diabetic retinopathy.

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

“…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.…”

“…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.…”

“…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].…”

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…145 In cultured mesangial cells, it has been suggested that high glucose-induced prorenin upregulation leads to the production of inflammatory cytokines, such as interleukin-1b and cyclooxygenase-2 (Huang and Siragy 146 ). In the retinal vasculature of diabetic mice, Satofuka et al 147 have shown that handle region peptides, also called (P)RR blockers (PRRBs), reduced leukostasis to a greater extent than the AT1-R blocker losartan in wild-type mice and also reduced leukostasis in AT1A receptor gene knockout mice. Furthermore, PRRB reduced the diabetes-induced elevation in retinal expression of phosphorylated extracellular signal-regulated kinases 1/2 in AT1A receptor gene knockout mice.…”

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

“…Recently, Matavelli et al 95 extended these mechanisms suggesting that the renal (pro)renin and (P)RR axis promotes diabetic nephropathy by significantly increasing the amounts of pro-inflammatory cytokines. The handle region peptide (HRP), a putative blocker of the (P)RR, could efficiently block glomerulosclerosis, 86,88,95,96 while RAS inhibitors were unable to prevent end-stage organ damage associated with diabetes. 97,98 However, not all investigators were able to reproduce the inhibitory effects of HRP either in vivo or in vitro.…”