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The renin-angiotensin system (RAS), a controller of systemic blood pressure (circulatory RAS), plays distinct roles in inflammation and angiogenesis in organs (tissue RAS). Pharmacological blockade of angiotensin II type 1 receptor inhibited the incidence and progression of diabetic retinopathy (DR) in recent clinical trials.1 We unravelled the molecular mechanisms in which tissue RAS causes retinal inflammation2 and the critical roles of (pro)renin receptor ((P)RR) in retinal RAS activation.3 (P)RR binds with prorenin to exert renin activity through the conformational change of the prorenin (for tissue RAS) instead of the proteolysis of the prorenin prosegment (for circulatory RAS). Furthermore, prorenin binding to (P)RR activates RAS-independent signal transduction. The (P)RR-mediated dual activation of tissue RAS and RAS-independent signalling pathways, referred to as the receptor-associated prorenin system (RAPS), was shown to facilitate vascular endothelial growth factor (VEGF)-driven pathogenesis of non-proliferative DR in mice.3
We further reported that the intravitreal levels of soluble form of (P)RR (s(P)RR), released from neovascular endothelial cells in fibrovascular tissues, increased in the patients with proliferative DR (PDR) and correlated with vitreous prorenin and VEGF levels.4 This leads to a novel concept for the molecular pathogenesis of tissue RAS …
Contributors AK and SI were responsible for the conception and design, AK, KN and WS performed analysis and interpretation of data described in the study, AK drafted the article, and KN, WS and SI contributed to discussion and reviewed the article. All authors approved the final version submitted for publication.
Funding This work was supported in part by the Matching Program for Innovations in Future Drug Discovery and Medical Care, Takeda Science Foundation, Mishima Saiichi Memorial Ophthalmic Research Japan Foundation, and a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to AK, No. 24791823).
Competing interests None.
Ethics approval The institutional review board of Hokkaido University Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.