Hokkaido University Graduate School of Medicine, Japan
Ishida undertook his residency in ophthalmology at Keio University Hospital after completing his medical degree at the age of 24 years. He completed fellowships in the Department of Ophthalmology at Keio University School of Medicine, and the Massachusetts Eye and Ear Infi rmary at Harvard Medical School, and received a Ph.D. from Keio University on the subject of vascular endothelial growth factor in diabetic retinopathy. Prof. Ishida is an author on over 150 scientifi c publications (impact factor: over 450) and currently Professor and Chairman of Ophthalmology at Hokkaido University Graduate School of Medicine in Sapporo, Japan.
The renin-angiotensin system (RAS) plays a potential 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 the signifi cant involvement of (pro) renin receptor [(P)RR] with retinal infl ammation in a rodent model of early diabetes. We herein aim to elucidate (P)RRassociated pathogenesis of fi brovascular proliferation, the late-stage angiogenic complication in human diabetic retinopathy. Vitreous fl uids from 23 eyes with proliferative diabetic retinopathy (PDR) and 16 controls with non-diabetic, idiopathic macular diseases (macular hole and epiretinal membrane) were collected and protein levels of soluble (P)RR were measured by ELISA, and immunofl uorescence was performed to assess localization of (P)RR and related molecules in fi brovascular tissues from PDR eyes. (P)RR immunoreactivity was detected in neovascular endothelial cells, co-localized with prorenin, phosphorylated extracellular signal-regulated kinase (ERK) and vascular endothelial growth factor (VEGF). Prorenin application to human retinal microvascular endothelial cells signifi cantly up regulated mRNA expression of VEGF, especially the VEGF165 isoform, which was abolished by (P)RR or ERK signaling blockade. Proteases known for the cleavage of (P)RR including furin were positive in endothelial cells in fi brovascular tissues. Protein levels of soluble (P)RR in the vitreous fluids were higher in PDR eyes than in non-diabetic control eyes, and were significantly correlated with vitreous prorenin and VEGF levels and the vascular density of fibrovascular tissues. Our data using human samples provide the first evidence that (P)RR is associated with angiogenic activity in PDR.