(Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy. Issue 1 (13th May 2018)

• Record Type: Journal Article
• Authors: Kanda, Atsuhiro; Ishida, Susumu
• Is Part Of: Journal of diabetes investigation. Volume 10:Issue 1(2019)
• Page Start: 6
• Page End: 17
• Publication Date: 2018-05-13
• Subjects: Diabetic retinopathy -- (Pro)renin receptor -- Receptor‐associated prorenin system; Diabetes -- Periodicals; Diabetes -- Research -- Periodicals; Diabetes Mellitus -- Periodicals; 616.462005
• DOI: 10.1111/jdi.12842
• Languages: English
• ISSNs: 2040-1116

Abstract

Abstract: The renin–angiotensin system (RAS), a crucial regulator of systemic blood pressure (circulatory RAS), plays distinct roles in pathological angiogenesis and inflammation in various organs (tissue RAS), such as diabetic microvascular complications. Using ocular clinical samples and animal disease models, we elucidated molecular mechanisms in which tissue RAS excites the expression of vascular endothelial growth factor (VEGF)‐A responsible for retinal inflammation and angiogenesis, the two major pathological events in diabetic retinopathy (DR). Furthermore, we showed the involvement of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction (e.g., extracellular signal‐regulated kinase); namely, the (P)RR‐induced dual pathogenic bioactivity referred to as the receptor‐associated prorenin system. Indeed, neovascular endothelial cells in the fibrovascular tissue collected from eyes with proliferative DR were immunoreactive for the receptor‐associated prorenin system components including prorenin, (P)RR, phosphorylated extracellular signal‐regulated kinase and VEGF‐A. Protein levels of soluble (P)RR increased with its positive correlations with prorenin, renin enzymatic activity and VEGF in the vitreous of proliferative DR eyes, suggesting a close link between (P)RR and VEGF‐A‐driven angiogenic activity. Furthermore, we revealed an unsuspected, PAPS‐independent role of (P)RR in glucose‐induced oxidative stress. Recently, we developed an innovative single‐strand ribonucleic acid interference molecule selectively targeting human and mouse (P)RR, and confirmed its efficacy in suppressing diabetes‐induced retinal inflammation in mice. Our data using clinical samples and animal models suggested the significant implication of (P)RR in the pathogenesis of DR, and the potential usefulness of the ribonucleic acid interference molecule as a therapeutic agent to attenuate ocular inflammation and angiogenesis. Abstract : In the present review, we discuss recent progress in the understanding of involvement of (pro)renin receptor in the pathogenesis of diabetic retinopathy, together with our effort to develop an innovative therapeutic agent against (pro)renin receptor.