title: Exendin-4 alleviates retinal vascular leakage by protecting the blood-retinal barrier and reducing retinal vascular permeability in diabetic Goto-Kakizaki rats.
abstract: The breakdown of the inner endothelial blood-retinal barrier (BRB) and subsequent retinal vascular leakage are the main causes of vision loss due to diabetic retinopathy (DR). Exendin-4 (E4) is a long-acting agonist of the glucagon-like peptide 1 hormone receptor (GLP-1R) that is widely used in clinics and has shown a neuroprotective effect. Our previous studies demonstrated the protective effect of E4 in early experimental DR; however, the molecular and cellular mechanisms that mediate this protective effect are not fully known. The BRB plays a key role in DR. We speculated that E4 may exert its protective effects on the BRB. To test this hypothesis, E4 (0.1 μg/2 μL/eye) or vehicle were intravitreally injected into diabetic Goto-Kakizaki(GK) rats and control animals. The results revealed that E4 significantly inhibited the reductions in electroretinogram (ERG) amplitudes in the GK rats, particularly in the b-wave and oscillatory potentials (OPs). E4 upregulated retinal GLP-1R expression and downregulated the expressions of placental growth factor (PLGF) and vascular endothelial growth factor (VEGF) via the ERK and AKT/PKB pathways. Decreases in tight junction protein (i.e., claudin-5 and occludin) expression and increases in Evans blue permeation (EBP) were inhibited by E4. Similar results were also found in primary rat Müller cells in high glucose concentration cultures in vitro. We conclude that E4 may protect the BRB from diabetic insults by decreasing PLGF and ICAM-1 expression and maintaining the integrity of the BRB. Thus, E4 treatment may be an effective therapeutic approach for DR.
authors.affiliation: Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, 12 Middle Wulumuqi Road, Shanghai, China.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Ophthalmology, First People's Hospital of Shanghai Affiliated with 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, 12 Middle Wulumuqi Road, 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, 12 Middle Wulumuqi Road, Shanghai, China. Electronic address: yewen0412@hotmail.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Ye
authors.affiliation: Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, 12 Middle Wulumuqi Road, Shanghai, China. Electronic address: yuzhang1020@gmail.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects*; D062507:Claudin-5 / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004596:Electroretinography / Q000187:drug effects; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D058449:Intravitreal Injections; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D062793:Occludin / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D012171:Retinal Vessels / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: D062507:Claudin-5; C491510:Cldn5 protein, rat; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D062793:Occludin; C568987:Ocln protein, rat; D010455:Peptides; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D018027:Receptors, Glucagon; D042461:Vascular Endothelial Growth Factor A; D014688:Venoms; C467498:vascular endothelial growth factor A, rat; D018799:Intercellular Adhesion Molecule-1; D000072483:Placenta Growth Factor; D000077270:Exenatide
keywords: Goto-Kakizaki (GK) rat; blood–retinal barrier; diabetic retinopathy; exendin-4; glucagon-like peptide 1 receptor; placental growth factor (PLGF)