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


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.
Satofuka
Shingo
S
Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan.
Ichihara
Atsuhiro
A
Nagai
Norihiro
N
Noda
Kousuke
K
Ozawa
Yoko
Y
Fukamizu
Akiyoshi
A
Tsubota
Kazuo
K
Itoh
Hiroshi
H
Oike
Yuichi
Y
Ishida
Susumu
S
D000818:Animals; D030801:Animals, Genetically Modified; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012083:Renin / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012160:Retina / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000093342:Prorenin Receptor
D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D012083:Renin; D019808:Losartan; D000093342:Prorenin Receptor