Man Wang1, Yangningzhi Wang1, Tianhua Xie1, Pengfei Zhan1, Jian Zou2, Xiaowei Nie2,3, Jun Shao1, Miao Zhuang1, Chengye Tan1, Jianxin Tan2, Youai Dai2, Jie Sun2, Jiantao Li4, Yuehua Li4, Qian Shi5, Jing Leng6, Xiaolu Wang7,8, Yong Yao9. 1. Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China. 2. Center of Clinical Research, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China. 3. Wuxi Institute of Translational Medicine, Wuxi, Jiangsu, People's Republic of China. 4. Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China. 5. Yixing Eye Hospital, Wuxi, Jiangsu, People's Republic of China. 6. Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China. 7. Center of Clinical Research, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China. xlwang@njmu.edu.cn. 8. Wuxi Institute of Translational Medicine, Wuxi, Jiangsu, People's Republic of China. xlwang@njmu.edu.cn. 9. Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China. yongyao@njmu.edu.cn.
Abstract
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.
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 diabeticrats. This response was ameliorated in diabeticrats 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.
Authors: Bing Luan; Young-Sil Yoon; John Le Lay; Klaus H Kaestner; Susan Hedrick; Marc Montminy Journal: Proc Natl Acad Sci U S A Date: 2015-12-07 Impact factor: 11.205