Prostaglandin E2/EP2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes.
AIMS/HYPOTHESIS
Diabetic retinopathy is a common microvascular complication of diabetes mellitus and is initiated by inflammation and apoptosis-associated retinal endothelial cell damage. Prostaglandin E2 (PGE2) has emerged as a critical regulator of these biological processes. We hypothesised that modulating PGE2 and its E-prostanoid receptor (EP2R) would prevent diabetes mellitus-induced inflammation and microvascular dysfunction.


METHODS
In a streptozotocin (STZ)-induced rat model of diabetes, rats received intravitreal injection of PGE2, butaprost (a PGE2/EP2R agonist) or AH6809 (an EP2R antagonist). Retinal histology, optical coherence tomography, ultrastructure of the retinal vascular and biochemical markers were assessed.


RESULTS
Intravitreal injection of PGE2 and butaprost significantly accelerated retinal vascular leakage, leucostasis and endothelial cell apoptosis in STZ-induced diabetic rats. This response was ameliorated in diabetic rats pre-treated with AH6809. In addition, pre-treatment of human retinal microvascular endothelial cells with AH6809 attenuated PGE2- and butaprost-induced activation of caspase 1, activation of the complex containing nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment domain (ASC), and activation of the EP2R-coupled cAMP/protein kinase A/cAMP response element-binding protein signalling pathway.


CONCLUSIONS/INTERPRETATION
The PGE2/EP2R signalling pathway is involved in STZ-induced diabetic retinopathy and could be considered as a potential target for diabetic retinopathy prevention and treatment.
['Wang|Man|M|', 'Wang|Yangningzhi|Y|', 'Xie|Tianhua|T|', 'Zhan|Pengfei|P|', 'Zou|Jian|J|', 'Nie|Xiaowei|X|', 'Shao|Jun|J|', 'Zhuang|Miao|M|', 'Tan|Chengye|C|', 'Tan|Jianxin|J|', 'Dai|Youai|Y|', 'Sun|Jie|J|', 'Li|Jiantao|J|', 'Li|Yuehua|Y|', 'Shi|Qian|Q|', 'Leng|Jing|J|', 'Wang|Xiaolu|X|', 'Yao|Yong|Y|0000-0002-5506-7101']
D000527:Alprostadil D000818:Animals D003921:Diabetes Mellitus, Experimental D003930:Diabetic Retinopathy D015232:Dinoprostone D006801:Humans D058847:Inflammasomes D008297:Male D051381:Rats D017207:Rats, Sprague-Dawley D058307:Receptors, Prostaglandin E, EP2 Subtype D015398:Signal Transduction D014822:Vitreous Body D044004:Xanthones
Diabetic retinopathy Inflammation Endothelial cell PGE2 Microvascular disease