Editorial Commentary Is (Pro)Renin Receptor a Multifunctional Receptor?

The existence of various components of the renin-angiotensin system in the eye has been known for more than a decade, and the importance of this system in ocular pathophysiology is a subject of active investigation.1 It has long been recognized that prorenin, an inactive precursor of renin, is elevated in the ocular fluids of patients with diabetic retinopathy.2 However, the pathophysiological implications of these elevated levels remained a mystery until the discovery of a specific receptor for renin and prorenin: the (pro)renin receptor [(P)RR].3 (P)RR is a 350–amino acid transmembrane protein which has been proposed to function by two distinct mechanisms: (1) by binding to (pro)renin, (P)RR activates renin’s enzymatic activity inherent in prorenin, leading to the generation of angiotensin II by a traditional renin-angiotensin system pathway at the cell/tissue level4; and (2) (pro)renin binding to (P)RR initiates a cascade of signaling events that are associated with profibrotic and proliferative actions, independent of angiotensin II.4 Although the action of (P)RR in the generation of Ang II is documented, its coupling to signaling pathways leading to vasodeleterious effects remains to be fully elucidated. This is, in part, due to lack of a reliable and selective (P)RR antagonist. A peptide segment corresponding to amino acids 10 to 19 of the prorenin prosegment, called handle region peptide (HRP), has gained significant interest as a (P)RR antagonist. HRP has been shown to inhibit prorenin binding to (P)RR, and thus nonproteolytic activation,5 and to be capable of preventing diabetic nephropathy and cardiac fibrosis.6 In the eye, HRP has also been shown to be beneficial in preventing ocular inflammation induced by endotoxin7 and diabetes,8 as well as pathological angiogenesis.9 However, the potential of HRP as a specific antagonist of (P)RR for treating these pathological conditions has met with skepticism, because several studies have failed to reproduce the inhibitory effects of HRP either in vivo or in vitro.10,11 It is in this context that the study of Wilkinson-Berka et al12 in this issue of Hypertension is relevant. They present exciting observations indicating that systemic administration of HRP reduces angiogenesis in developing rodent retina, diminishes pathological angiogenesis, and reduces leukostasis and expression of inflammatory markers in rodents with oxygen-induced retinopathy. Thus, HRP exhibits a protective effect in retinal vasculature similar to the angiotensin II type 1 receptor blocker valsartan. These findings confirm previous reports by Satofuka et al.8,13 However, in contrast to previous reports on (P)RR’s cellular localization, in which it was detected mainly in the retinal vessels, Wilkinson-Berka12 et al found more abundant expression of (P)RR in retina neuro-glia. Moreover, they also revealed that HRP treatment in normal animals resulted in reduced electroretinogram responses. Because treatment with valsartan did not have any effect on electroretinogram, the detrimental effect of HRP on retinal function is likely mediated by an angiotensin II–independent mechanism, presumably via (P)RR. The cellular localization of (P)RR in retinal neuro-glia reported in this study is consistent with its involvement. Also consistent with this interpretation is the observation that elevated levels of (P)RR mRNA and phosphorylated extracellular-signal–related protein kinase (ERK) 1/2 immunolabeling in oxygen-induced retinopathy are reduced with HRP treatment. However, HRP was shown to increase (P)RR mRNA and phosphorylated ERK1/2 immunolabeling in the normal retina, an effect opposite that seen in the oxygen-induced retinopathy retina. These findings demonstrate the involvement of (P)RR in retinal pathophysiology and suggest that (P)RR may be multifunctional, exerting distinct actions with opposing effects in a cell-type specific manner. This study raises important questions that will determine the future direction in establishing the role of (P)RR and HRP. First, how does HRP exert its actions in the retina? The observation that no HRP is detectable in the circulation following continuous subcutaneous administration of the peptide, which contradicts a previous study,8 may indicate a methodological issue, as suggested in this study. However, a selective increase in the local HRP cannot be ruled out; if this is the case, the transport of HRP across the blood-retina barrier needs to be addressed. Furthermore, the possibility of a compromised blood-retina barrier under pathological conditions, such as diabetes, endotoxin presence, and pathological angiogenesis, would enable circulating HRP to accumulate in retinal tissue at concentrations appropriate for its actions. Second, do the opposing effects of HRP, ie, beneficial in retinal vasculature but detrimental in retinal neuro-glia, involve (P)RR? The observation that reduced electroretinogram following HRP treatment correlates with increased (P)RR mRNA and increased phosphorylated ERK1/2 immunostaining in the normal retina, but with reduced (P)RR mRNA and ERK1/2 immunolabeling in retinas with oxygen-induced retinopathy, supports the involvement of (P)RR. However, direct evidence that these effects are indeed mediated through The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Departments of Ophthalmology (Q.L.) and Physiology and Functional Genomics (M.K.R.), University of Florida College of Medicine, Gainesville, Fla. Correspondence to Mohan K. Raizada, Department of Physiology and Functional Genomics, University of Florida, PO Box 100274, Gainesville, FL 32610-0274. E-mail [email protected] (Hypertension. 2010;55:1308-1309.) © 2010 American Heart Association, Inc.