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

  1. Shingo Satofuka1,2,
  2. Atsuhiro Ichihara3,
  3. Norihiro Nagai1,2,
  4. Kousuke Noda1,2,
  5. Yoko Ozawa1,2,
  6. Akiyoshi Fukamizu4,
  7. Kazuo Tsubota2,
  8. Hiroshi Itoh3,
  9. Yuichi Oike5 and
  10. Susumu Ishida1,2,6
  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.
  1. Corresponding author: Susumu Ishida, ishidasu{at}sc.itc.keio.ac.jp.


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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  • See accompanying commentary, p. 1485.

    • Received February 21, 2008.
    • Accepted March 27, 2009.
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