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Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line.
Diabetologia. 2011 Jun; 54(6):1567-78.D

Abstract

AIMS/HYPOTHESIS

Recent studies have demonstrated that cannabinoid-1 (CB(1)) 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 pro-apoptotic 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.

Authors+Show Affiliations

Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21373835

Citation

El-Remessy, A B., et al. "Cannabinoid 1 Receptor Activation Contributes to Vascular Inflammation and Cell Death in a Mouse Model of Diabetic Retinopathy and a Human Retinal Cell Line." Diabetologia, vol. 54, no. 6, 2011, pp. 1567-78.
El-Remessy AB, Rajesh M, Mukhopadhyay P, et al. Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line. Diabetologia. 2011;54(6):1567-78.
El-Remessy, A. B., Rajesh, M., Mukhopadhyay, P., Horváth, B., Patel, V., Al-Gayyar, M. M., Pillai, B. A., & Pacher, P. (2011). Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line. Diabetologia, 54(6), 1567-78. https://doi.org/10.1007/s00125-011-2061-4
El-Remessy AB, et al. Cannabinoid 1 Receptor Activation Contributes to Vascular Inflammation and Cell Death in a Mouse Model of Diabetic Retinopathy and a Human Retinal Cell Line. Diabetologia. 2011;54(6):1567-78. PubMed PMID: 21373835.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line. AU - El-Remessy,A B, AU - Rajesh,M, AU - Mukhopadhyay,P, AU - Horváth,B, AU - Patel,V, AU - Al-Gayyar,M M H, AU - Pillai,B A, AU - Pacher,P, Y1 - 2011/03/04/ PY - 2010/11/30/received PY - 2010/12/30/accepted PY - 2011/3/5/entrez PY - 2011/3/5/pubmed PY - 2011/9/9/medline SP - 1567 EP - 78 JF - Diabetologia JO - Diabetologia VL - 54 IS - 6 N2 - AIMS/HYPOTHESIS: Recent studies have demonstrated that cannabinoid-1 (CB(1)) 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 pro-apoptotic 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. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/21373835/Cannabinoid_1_receptor_activation_contributes_to_vascular_inflammation_and_cell_death_in_a_mouse_model_of_diabetic_retinopathy_and_a_human_retinal_cell_line_ L2 - https://doi.org/10.1007/s00125-011-2061-4 DB - PRIME DP - Unbound Medicine ER -