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      (Pro)renin Receptor–Mediated Signal Transduction and Tissue Renin-Angiotensin System Contribute to Diabetes-Induced Retinal Inflammation

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          Abstract

          OBJECTIVE

          The term “receptor-associated prorenin system” (RAPS) refers to the pathogenic mechanisms whereby prorenin binding to its receptor dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor. The aim of the present study was to define the association of the RAPS with diabetes-induced retinal inflammation.

          RESEARCH DESIGN AND METHODS

          Long-Evans rats, C57BL/6 mice, and angiotensin II type 1 receptor (AT1-R)-deficient mice with streptozotocin-induced diabetes were treated with (pro)renin receptor blocker (PRRB). Retinal mRNA expression of prorenin and the (pro)renin receptor was examined by quantitative RT-PCR. Leukocyte adhesion to the retinal vasculature was evaluated with a concanavalin A lectin perfusion–labeling technique. Retinal protein levels of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1 were examined by ELISA. Retinal extracellular signal–regulated kinase (ERK) activation was analyzed by Western blotting.

          RESULTS

          Induction of diabetes led to significant increase in retinal expression of prorenin but not the (pro)renin receptor. Retinal adherent leukocytes were significantly suppressed with PRRB. Administration of PRRB inhibited diabetes-induced retinal expression of VEGF and ICAM-1. To clarify the role of signal transduction via the (pro)renin receptor in the diabetic retina, we used AT1-R–deficient mice in which the RAS was deactivated. Retinal adherent leukocytes in AT1-R–deficient diabetic mice were significantly suppressed with PRRB. PRRB suppressed the activation of ERK and the production of VEGF, but not ICAM-1, in AT1-R–deficient diabetic mice.

          CONCLUSIONS

          These results indicate a significant contribution of the RAPS to the pathogenesis of diabetes-induced retinal inflammation, suggesting the possibility of the (pro)renin receptor as a novel molecular target for the treatment of diabetic retinopathy.

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          A central role for inflammation in the pathogenesis of diabetic retinopathy.

          Antonia Joussen, Vassiliki Poulaki, Minh Ly Le … (2004)
          Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. Diabetic retinal vascular leakage, capillary nonperfusion, and endothelial cell damage are temporary and spatially associated with retinal leukocyte stasis in early experimental diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1) and CD18. Mice deficient in the genes encoding for the leukocyte adhesion molecules CD18 and ICAM-1 were studied in two models of diabetic retinopathy with respect to the long-term development of retinal vascular lesions. CD18-/- and ICAM-1-/- mice demonstrate significantly fewer adherent leukocytes in the retinal vasculature at 11 and 15 months after induction of diabetes with STZ. This condition is associated with fewer damaged endothelial cells and lesser vascular leakage. Galactosemia of up to 24 months causes pericyte and endothelial cell loss and formation of acellular capillaries. These changes are significantly reduced in CD18- and ICAM-1-deficient mice. Basement membrane thickening of the retinal vessels is increased in long-term galactosemic animals independent of the genetic strain. Here we show that chronic, low-grade subclinical inflammation is responsible for many of the signature vascular lesions of diabetic retinopathy. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-inflammatory treatment in diabetic retinopathy.
          Article 0 comments Cited 347 times – based on 0 reviews     Review now
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            Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition.

            K Miyamoto, S Khosrof, S E Bursell … (1999)
            Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. This study shows that diabetic retinal vascular leakage and nonperfusion are temporally and spatially associated with retinal leukocyte stasis (leukostasis) in the rat model of streptozotocin-induced diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1). ICAM-1 blockade with a mAb prevents diabetic retinal leukostasis and vascular leakage by 48.5% and 85.6%, respectively. These data identify the causal role of leukocytes in the pathogenesis of diabetic retinopathy and establish the potential utility of ICAM-1 inhibition as a therapeutic strategy for the prevention of diabetic retinopathy.
            Article 0 comments Cited 140 times – based on 0 reviews     Review now
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              Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo.

              Antonia Joussen, Vassiliki Poulaki, Wenying Qin … (2002)
              Leukocyte adhesion to the diabetic retinal vasculature results in early blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell injury and death. Previous work has shown that intercellular adhesion molecule-1 (ICAM-1) and CD18 are required for these processes. However the relevant in vivo stimuli for ICAM-1 and CD18 expression in diabetes remain unknown. The current study investigated the causal role of endogenous vascular endothelial growth factor (VEGF) and nitric oxide in initiating these events. Diabetes was induced in Long-Evans rats with streptozotocin, resulting in a two- to threefold increase in retinal leukocyte adhesion. Confirmed diabetic animals were treated with a highly specific VEGF-neutralizing Flt-Fc construct (VEGF TrapA(40)). Retinal ICAM-1 mRNA levels in VEGF TrapA(40)-treated diabetic animals were reduced by 83.5% compared to diabetic controls (n = 5, P < 0.0001). VEGF TrapA(40) also potently suppressed diabetic leukocyte adhesion in retinal arterioles (47%, n = 11, P < 0.0001), venules (36%, n = 11, P < 0.0005), and capillaries (36%, n = 11, P < 0.001). The expression of endothelial nitric oxide synthase (eNOS), a downstream mediator of VEGF activity, was increased in diabetic retina, and was potently suppressed with VEGF TrapA(40) treatment (n = 8, P < 0.005). Further, VEGF TrapA(40) reduced the diabetes-related nitric oxide increases in the retinae of diabetic animals. The inhibition of eNOS with N-omega-nitro-L-arginine methyl ester also potently reduced retinal leukocyte adhesion. Although neutrophil CD11a, CD11b, and CD18 levels were increased in 1-week diabetic animals, VEGF TrapA(40) did not alter the expression of these integrin adhesion molecules. Taken together, these data demonstrate that VEGF induces retinal ICAM-1 and eNOS expression and initiates early diabetic retinal leukocyte adhesion in vivo. The inhibition of VEGF bioactivity may prove useful in the treatment of the early diabetic retinopathy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes
                Journal ID (hwp): diabetes
                Journal ID (pmc): diabetes
                Journal ID (publisher-id): Diabetes
                Title: Diabetes
                Publisher: American Diabetes Association
                ISSN (Print): 0012-1797
                ISSN (Electronic): 1939-327X
                Publication date (Print): July 2009
                Publication date (Electronic): 23 April 2009
                Volume: 58
                Issue: 7
                Pages: 1625-1633
                Affiliations
                [1] 1Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan;
                [2] 2Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan;
                [3] 3Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan;
                [4] 4Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan;
                [5] 5Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;
                [6] 6Inaida Endowed Department of Anti-Aging Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
                Author notes
                Corresponding author: Susumu Ishida, ishidasu@ 123456sc.itc.keio.ac.jp .
                Article
                Publisher ID: 0254
                DOI: 10.2337/db08-0254
                PMC ID: 2699867
                PubMed ID: 19389828
                SO-VID: ecd55a07-80cc-4f8b-9905-4249dc87afaa
                Copyright © © 2009 by the American Diabetes Association.
                License:

                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.

                History
                Date received : 21 February 2008
                Date accepted : 27 March 2009
                Categories
                Subject: Original Article
                Subject: Complications

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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