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

Shingo Satofuka, Atsuhiro Ichihara, Norihiro Nagai, Kousuke Noda, Yoko Ozawa, Akiyoshi Fukamizu, Kazuo Tsubota, Hiroshi Itoh, Yuichi Oike, Susumu Ishida

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1625-1633
Number of pages9
JournalDiabetes
Volume58
Issue number7
DOIs
Publication statusPublished - 2009 Jul

Fingerprint

Renin-Angiotensin System
Renin
Signal Transduction
Inflammation
Angiotensin Type 1 Receptor
Intercellular Adhesion Molecule-1
Vascular Endothelial Growth Factor A
Leukocytes
Extracellular Signal-Regulated MAP Kinases
Long Evans Rats
Experimental Diabetes Mellitus
prorenin receptor
Diabetic Retinopathy
Concanavalin A
Inbred C57BL Mouse
Lectins
Retina
Research Design
Perfusion
Western Blotting

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

(Pro)renin receptor-mediated signal transduction and tissue renin-angiotensin system contribute to diabetes-induced retinal inflammation. / Satofuka, Shingo; Ichihara, Atsuhiro; Nagai, Norihiro; Noda, Kousuke; Ozawa, Yoko; Fukamizu, Akiyoshi; Tsubota, Kazuo; Itoh, Hiroshi; Oike, Yuichi; Ishida, Susumu.

In: Diabetes, Vol. 58, No. 7, 07.2009, p. 1625-1633.

Research output: Contribution to journalArticle

Satofuka, Shingo ; Ichihara, Atsuhiro ; Nagai, Norihiro ; Noda, Kousuke ; Ozawa, Yoko ; Fukamizu, Akiyoshi ; Tsubota, Kazuo ; Itoh, Hiroshi ; Oike, Yuichi ; Ishida, Susumu. / (Pro)renin receptor-mediated signal transduction and tissue renin-angiotensin system contribute to diabetes-induced retinal inflammation. In: Diabetes. 2009 ; Vol. 58, No. 7. pp. 1625-1633.
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AU - Satofuka, Shingo

AU - Ichihara, Atsuhiro

AU - Nagai, Norihiro

AU - Noda, Kousuke

AU - Ozawa, Yoko

AU - Fukamizu, Akiyoshi

AU - Tsubota, Kazuo

AU - Itoh, Hiroshi

AU - Oike, Yuichi

AU - Ishida, Susumu

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