Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line

A. B. El-Remessy, M. Rajesh, P. Mukhopadhyay, B. Horváth, V. Patel, M. M.H. Al-Gayyar, B. A. Pillai, P. Pacher

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

Abstract

Aims/hypothesis: Recent studies have demonstrated that cannabinoid-1 (CB1) receptor blockade ameliorated inflammation, endothelial and/or cardiac dysfunction, and cell death in models of nephropathy, atherosclerosis and cardiomyopathy. However the role of CB 1 receptor signalling in diabetic retinopathy remains unexplored. Using genetic deletion or pharmacological inhibition of the CB 1 receptor with SR141716 (rimonabant) in a rodent model of diabetic retinopathy or in human primary retinal endothelial cells (HREC) exposed to high glucose, we explored the role of CB 1 receptors in the pathogenesis of diabetic retinopathy. Methods: Diabetes was induced using streptozotocin in C57BL/6J Cb 1 (also known as Cnr1) +/+ and Cb 1 -/- mice aged 8 to 12 weeks. Samples from mice retina or HREC were used to determine: (1) apoptosis; (2) activity of nuclear factor kappa B, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), poly (ADP-ribose) polymerase and caspase-3; (3) content of 3-nitrotyrosine and reactive oxygen species; and (4) activation of p38/Jun N-terminal kinase/mitogen-activated protein kinase (MAPK). Results: Deletion of CB 1 receptor or treatment of diabetic mice with CB 1 receptor antagonist SR141716 prevented retinal cell death. Treatment of diabetic mice or HREC cells exposed to high glucose with SR141716 attenuated the oxidative and nitrative stress, and reduced levels of nuclear factor κB, ICAM-1 and VCAM-1. In addition, SR141716 attenuated the diabetes- or high glucose-induced proapoptotic activation of MAPK and retinal vascular cell death. Conclusions/interpretation: Activation of CB 1 receptors may play an important role in the pathogenesis of diabetic retinopathy by facilitating MAPK activation, oxidative stress and inflammatory signalling. Conversely, CB 1 receptor inhibition may be beneficial in the treatment of this devastating complication of diabetes.

Original languageEnglish
Pages (from-to)1567-1578
Number of pages12
JournalDiabetologia
Volume54
Issue number6
DOIs
Publication statusPublished - Jun 2011
Externally publishedYes

Keywords

  • Apoptosis
  • CB
  • Cannabinoid
  • ICAM-1
  • NFκB
  • Rimonabant
  • SR141716
  • VCAM-1

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Fingerprint

Dive into the research topics of 'Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line'. Together they form a unique fingerprint.

Cite this