title: Exendin-4 protects retinal cells from early diabetes in Goto-Kakizaki rats by increasing the Bcl-2/Bax and Bcl-xL/Bax ratios and reducing reactive gliosis.
abstract: OBJECTIVE
  Exendin-4 (E4), a long-acting agonist of the hormone glucagon-like peptide 1 receptor (GLP-1R), is administered to treat type II diabetes in the clinical setting and also shows a neuroprotective effect. Our previous studies demonstrated its protective effect in early experimental diabetic retinopathy (DR), but the molecular and cellular mechanisms are largely unknown. This study aimed to investigate the protective mechanism of a GLP-1R agonist E4 against early DR in Goto-Kakizaki (GK) rats.
  
  
  METHODS
  Diabetic GK rats and control animals were randomly assigned to receive E4 or vehicle by intravitreal injection. The retinal function and retinal cell counts were evaluated using an electroretinogram and light microscopy. The expressions of retinal GLP-1R, mitochondria-dependent apoptosis-associated genes, reactive gliosis markers, and endoplasmic reticulum stress-related pathway genes were studied by western blotting and immunohistochemistry in vivo and in vitro.
  
  
  RESULTS
  E4 significantly prevented the reduction of the b-wave and oscillatory potential amplitudes and retinal cell loss and maintained the Bcl-2/Bax and Bcl-xL/Bax ratio balances in GK rats. It also downregulated the expression of glial fibrillary acidic protein and reduced retinal reactive gliosis. Similar results were found in primary rat Müller cells under high glucose culture in vitro.
  
  
  CONCLUSIONS
  E4 may protect retinal cells from diabetic attacks by activating GLP-1R, decreasing retinal cell apoptosis, and reducing retinal reactive gliosis. Thus, E4 treatment may be a novel approach for early DR.
authors.affiliation: Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Ophthalmology, First People's Hospital of Shanghai affiliated to Shanghai Jiaotong University, Shanghai, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Qingping
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Glycoconjugate Research, Ministry of Public Health, Shanghai Medical College of Fudan University, Shanghai, China ; Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Ye
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004596:Electroretinography; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077270:Exenatide; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005911:Gliosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D058449:Intravitreal Injections; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D061251:Primary Cell Culture; D020011:Protective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D018027:Receptors, Glucagon / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014688:Venoms / Q000494:pharmacology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D005947:Glucose