(Pro)renin receptor-mediated signal transduction and tissue renin-angiotensin system contribute to diabetes-induced retinal inflammation

Diabetes. 2009 Jul;58(7):1625-33. doi: 10.2337/db08-0254. Epub 2009 Apr 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Intercellular Adhesion Molecule-1 / metabolism
  • Losartan / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • Rats
  • Rats, Long-Evans
  • Receptor, Angiotensin, Type 1 / deficiency
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / physiology*
  • Renin / genetics
  • Renin / metabolism
  • Renin / physiology
  • Retina / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • RNA, Messenger
  • Receptor, Angiotensin, Type 1
  • Receptors, Cell Surface
  • Vascular Endothelial Growth Factor A
  • prorenin receptor
  • Intercellular Adhesion Molecule-1
  • Renin
  • Losartan