Hyperglycemia induces apoptosis via CB1 activation through the decrease of FAAH 1 in retianl pigment epithelial cells

Title
Hyperglycemia induces apoptosis via CB1 activation through the decrease of FAAH 1 in retianl pigment epithelial cells
Author(s)
임슬기[임슬기]박민정[박민정]임재청[임재청]김종천[김종천]한호재[한호재]김계엽[김계엽]벤자민 크레벳[벤자민 크레벳]우창훈마승진[마승진]윤경철[윤경철]박수현[박수현]
Keywords
ACID AMIDE HYDROLASE; ENDOPLASMIC-RETICULUM STRESS; DIABETIC-RETINOPATHY; MITOCHONDRIAL DYSFUNCTION; CANNABINOID RECEPTOR; ENDOCANNABINOID SYSTEM; NITRIC-OXIDE; RAT RETINA; GLUCOSE; EXPRESSION
Issue Date
201202
Publisher
WILEY-BLACKWELL
Citation
JOURNAL OF CELLULAR PHYSIOLOGY, v.227, no.2, pp.569 - 577
Abstract
Fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the main endocannabinoid, anandamide, and related fatty acid amides, has emerged as a regulator of endocannabinoid signaling. Retinal pigment epithelial (RPE) cells are believed to be important cells in the pathogenesis of diabetic retinopathy. However, the pathophysiology of FAAH in diabetic retinopathy has not been determined. Thus, we examined the effect of high glucose (HG) on the expression of FAAH and CB1R in the ARPE-19 human RPE cells. We found that HG downregulated the expression of FAAH 1 mRNA and protein in ARPE-19 cells. In contrast, it upregulated the expression of CB1R mRNA and protein. HG-induced internalization of CB1R in HEK 293 cells and ARPE-19 cells was blocked by overexpression of FAAH 1 and treatment with the CB1R blocker, AM 251. HG-induced generation of reactive oxygen species and lipid peroxide formation were blocked by the overexpression of FAAH 1. FAAH 1 overexpression also blocked HG-induced expression of CB1R in the cytosolic fraction. We also investigated whether the overexpression of FAAH 1 protected against HG-induced apoptosis. High glucose increased the Bax/Bcl-2 ratio and levels of cleaved PARP, cleaved caspase-9 and caspase-3, and reduced cell viability. HG-induced apoptotic effects were reduced by the overexpression of FAAH 1, treatment with the CB1R-specific antagonist AM 251 and CB1R siRNA transfection. In conclusion, HG-induced apoptosis in ARPE-19 cells by inducing CB1R expression through the downregulation of FAAH 1 expression. Our results provide evidence that CB1R blockade through the recovery of FAAH 1 expression may be a potential anti-diabetic therapy for the treatment of diabetic retinopathy. J. Cell. Physiol. 227: 569577, 2012. (C) 2011 Wiley Periodicals, Inc.
URI
http://hdl.handle.net/YU.REPOSITORY/29810http://dx.doi.org/10.1002/jcp.22756
ISSN
0021-9541
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의과대학 > 약리학교실 > Articles
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