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Diabetologia

, Volume 62, Issue 2, pp 335–348 | Cite as

Prostaglandin E2/EP2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes

  • Man Wang
  • Yangningzhi Wang
  • Tianhua Xie
  • Pengfei Zhan
  • Jian Zou
  • Xiaowei Nie
  • Jun Shao
  • Miao Zhuang
  • Chengye Tan
  • Jianxin Tan
  • Youai Dai
  • Jie Sun
  • Jiantao Li
  • Yuehua Li
  • Qian Shi
  • Jing Leng
  • Xiaolu WangEmail author
  • Yong YaoEmail author
Article

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.

Keywords

Diabetic retinopathy Endothelial cell Inflammation Microvascular disease PGE2 

Abbreviations

ASC

Apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment domain

COX-2

Cyclooxygenase-2

CREB

cAMP response element-binding protein

EP1–4R

E-prostanoid1–4 receptor

hRMEC

Human RMEC

LDH

Lactate dehydrogenase

NLRP3

Nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3

OCT

Optical coherence tomography

PGE2

Prostaglandin E2

PKA

Protein kinase A

RMEC

Retinal microvascular endothelial cell

STZ

Streptozotocin

z-VAD

Z-YVAD-fmk

Notes

Contribution statement

XW and YY made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content. MW, YW, TX and PZ made substantial contributions to acquisition of data, analysis and interpretation of data and revising the article critically for important intellectual content. JZ, XN, JLi, YL, QS and JLeng made substantial contributions to conception and design, analysis and interpretation of data and revising the article critically for important intellectual content. JShao, MZ and CT made substantial contributions to conception and design, acquisition of data and revising the article critically for important intellectual content. JT, YD and JSun made substantial contributions to conception and design, analysis and interpretation of data and revising the manuscript critically for important intellectual content. All authors gave final approval of the version to be published. XW had full access to all the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

This work was supported by grants from the National Natural Science Foundation of China (no. 81770941), Jiangsu Key Medical Disciplines (ZDXKC2016008), Technology Development Fund (CSE12N1701) and Wuxi Eminent Medical Talents (JCRC005).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4755_MOESM1_ESM.pdf (894 kb)
ESM (PDF 894 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Man Wang
    • 1
  • Yangningzhi Wang
    • 1
  • Tianhua Xie
    • 1
  • Pengfei Zhan
    • 1
  • Jian Zou
    • 2
  • Xiaowei Nie
    • 2
    • 3
  • Jun Shao
    • 1
  • Miao Zhuang
    • 1
  • Chengye Tan
    • 1
  • Jianxin Tan
    • 2
  • Youai Dai
    • 2
  • Jie Sun
    • 2
  • Jiantao Li
    • 4
  • Yuehua Li
    • 4
  • Qian Shi
    • 5
  • Jing Leng
    • 6
  • Xiaolu Wang
    • 2
    • 3
    Email author
  • Yong Yao
    • 1
    Email author
  1. 1.Department of OphthalmologyWuxi People’s Hospital Affiliated to Nanjing Medical UniversityWuxiPeople’s Republic of China
  2. 2.Center of Clinical ResearchWuxi People’s Hospital Affiliated to Nanjing Medical UniversityWuxiPeople’s Republic of China
  3. 3.Wuxi Institute of Translational MedicineWuxiPeople’s Republic of China
  4. 4.Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of PathophysiologyNanjing Medical UniversityNanjingPeople’s Republic of China
  5. 5.Yixing Eye HospitalWuxiPeople’s Republic of China
  6. 6.Cancer Center, Department of PathologyNanjing Medical UniversityNanjingPeople’s Republic of China

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