(Pro)renin Receptor: A Treatment Target for Diabetic Retinopathy?

Many lines of evidence implicate the reninangiotensin system in the pathogenesis of diabetic retinopathy. A recent multicenter trial showed that angiotensin II type 1 (AT1) receptor blockade (ARB) reduced the incidence of retinopathy in type 1 diabetic patients and improved the regression of retinal disease in type 2 diabetic patients (1,2). However, the failure of ARB to prevent progression of diabetic retinopathy indicates a role for mechanisms additional to angiotensin II in its pathogenesis. In this issue of Diabetes, Satofuka et al. (3) provide evidence that prorenin and the (pro)renin receptor, acting in part through mechanisms unrelated to angiotensin II, may contribute to the pathogenesis of diabetic retinopathy. This evidence holds promise for new therapies for diabetic retinopathy and other complications of diabetes. Prorenin is a high–molecular weight biosynthetic precursor of renin. It has a low intrinsic activity of 2% of the activity of renin (4) because it has an amino-terminal 43–amino acid prosegment that masks the active site, thereby preventing access by the renin substrate—angiotensinogen. Renal juxtaglomerular cells are the only known site of renin production, whereas the kidney and a number of extrarenal tissues including adrenal, ovary, testis, placenta, and retina produce prorenin (5–7). Plasma prorenin concentrations are 10to 20-fold higher than those of renin (4). Prorenin concentrations in plasma and vitreous fluid are increased in diabetic subjects (6,8), and plasma prorenin is a powerful marker for both prevalent and incident microvascular complications of diabetes, including nephropathy, retinopathy, and neuropathy (9,10). Before the discovery of the (pro)renin receptor, there was uncertainty regarding whether prorenin was biologically active (4). The (pro)renin receptor binds both renin and prorenin and is reported to increase the catalytic efficiency of renin and activate prorenin (11). Thus, binding of renin and prorenin not only stimulates the (pro)renin receptor but also increases angiotensin II formation, leading to AT1 receptor stimulation (Fig. 1). Suzuki et al. (12) proposed that a region of the prorenin prosegment, called the handle region, participates in the binding of prorenin to its receptor. They further suggested that synthetic handle region peptides (HRPs), corresponding to amino acids 10–19 of the prorenin prosegment, interfere with prorenin binding. In support of this hypothesis, they showed that HRP blocked the binding of prorenin to recombinant prorenin receptors expressed by COS-7 cells, with a Ki of 6.6 nmol/l (13). Ichihara et al. (14) tested this hypothesis in vivo by administering HRP to various experimental models of disease; rat HRP completely prevented the development of nephropathy in diabetic rats and caused regression of established diabetic nephropathy (15). HRP is referred to as (pro)renin receptor blocker (PRRB) in the current study by Satofuka et al. (3). In an elegant series of experiments, Satofuka et al. (3) showed that PRRB reduced leukostasis in retinal vasculature of diabetic rats and mice; PRRB reduced leukostasis to a greater extent than the ARB losartan in wild-type mice and also reduced leukostasis in AT1A receptor gene knockout mice. In addition, PRRB reduced the diabetesinduced elevation in retinal expression of vascular endothelial growth factor (VEGF) and intracellular adhesion molecule-1 (ICAM-1) in wild-type mice and VEGF but not ICAM-1 expression in AT1A receptor gene knockout mice. Moreover, PRRB reduced the diabetes-induced elevation in retinal expression of phosphorylated extracellular signal–related kinase (ERK)1/2 in AT1A receptor gene knockout mice. The finding that PRRB reduced phosphorylated ERK1/2 expression in cultured brain capillary endothelial cells stimulated with prorenin, but not in cells stimulated with angiotensin II, was consistent with a specific effect of PRRB on the actions of prorenin. Satofuka et al. (3) did not evaluate retinal neovascularization because diabetic rodents do not develop proliferative diabetic retinopathy. However, it is important to note that PRRB attenuated neovascularization in other models of ocular disease (16). Also relevant to diabetic retinopathy are previous studies showing that prorenin, renin, and angiotensin II are expressed in ganglion cells and Müller cells in adult and neonatal rat retina (17). Given that neuronal and glial dysfunction contribute to diabetic retinopathy, which can be prevented by ARB (18), it is important to determine whether PRRB has similar protective effects. A critical question in the interpretation of these data is whether the actions of PRRB demonstrate a role for prorenin and the (pro)renin receptor in diabetic retinopathy. Satofuka et al. showed that PRRB reduced the immunostaining of retinal vessels by an antibody directed to the prorenin prosegment (3). In the absence of evidence for specificity of immunostaining, additional information would have been helpful, such as immunostaining with an antibody that recognized both renin and prorenin. Moreover, measurement of retinal angiotensin peptides might have clarified the effects of PRRB on angiotensin formation in the retina. From the Department of Immunology, Monash University, Prahran, Victoria, Australia; and the St. Vincent’s Institute of Medical Research and Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, Australia. Corresponding author: Jennifer L. Wilkinson-Berka, jennifer.wilkinson-berka@ med.monash.edu.au. DOI: 10.2337/db09-0604 © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 1625. COMMENTARY