Protective effects of the dipeptidyl peptidase IV inhibitor sitagliptin in the blood-retinal barrier in a type 2 diabetes animal model

Aim: The aim of this study was to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV inhibitor (DPP‐IV), in preventing the deleterious effects of diabetes on the blood–retinal barrier in male Zucker Diabetic Fatty (ZDF) rats. Methods: ZDF rats at 20 weeks of age were treated with sitagl...

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Published in:Diabetes, obesity & metabolism obesity & metabolism, 2012-05, Vol.14 (5), p.454-463
Main Authors: Gonçalves, A., Leal, E., Paiva, A., Teixeira Lemos, E., Teixeira, F., Ribeiro, C. F., Reis, F., Ambrósio, A. F., Fernandes, R.
Format: Article
Language:English
Subjects:
Animal models
Animals
Apoptosis
Blood glucose
Blood vessels
blood-retinal barrier
Blood-Retinal Barrier - drug effects
Blood-Retinal Barrier - metabolism
Blotting, Western
CD34 antigen
Cell death
Diabetes
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Experimental - drug therapy
diabetic retinopathy
Diabetic Retinopathy - drug therapy
Dipeptidyl-peptidase IV
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
DNA nucleotidylexotransferase
endothelial progenitor cells
Flow cytometry
Glycated Hemoglobin A - drug effects
Hemoglobin
Immunohistochemistry
In Situ Nick-End Labeling
Inflammation
Labeling
Male
Nitrotyrosine
Progenitor cells
Pyrazines - pharmacology
Rats
Rats, Zucker
Retina
sitagliptin
Sitagliptin Phosphate
Triazoles - pharmacology
Western blotting
Zucker Diabetic Fatty rat
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Summary:Aim: The aim of this study was to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV inhibitor (DPP‐IV), in preventing the deleterious effects of diabetes on the blood–retinal barrier in male Zucker Diabetic Fatty (ZDF) rats. Methods: ZDF rats at 20 weeks of age were treated with sitagliptin (10 mg/kg/day) during 6 weeks. The effect of the drug on glycaemia was assessed by evaluating glycated haemoglobin (HbA1c). The content and/or distribution of tight junction (TJ) proteins occludin and claudin‐5, as well as nitrotyrosine residues, interleukin (IL)‐1β, BAX and Bcl‐2 was evaluated in the retinas by western blotting and/or immunohistochemistry. Retinal cell apoptosis was assessed by the terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling (TUNEL) assay. The number of CD34+ cells present in peripheral circulation was assessed by flow cytometry, and endothelial progenitor cells (EPC) adhesion ability to the retinal vessels was evaluated by immunohistochemistry. Results: Sitagliptin improved glycaemic control as reflected by a significant decrease in HbA1c levels by about 1.2%. Treatment with sitagliptin prevented the changes in the endothelial subcellular distribution of the TJ proteins induced by diabetes. Sitagliptin also decreased the nitrosative stress, the inflammatory state and cell death by apoptosis in diabetic retinas. Diabetic animals presented decreased levels of CD34+ cells in the peripheral circulation and decreased adhesion ability of EPC to the retinal vessels. Sitagliptin allowed a recovery of the number of CD34+ cells present in the bloodstream to levels similar to their number in controls and increased the adhesion ability of EPC to the retinal vessels. Conclusions: Sitagliptin prevented nitrosative stress, inflammation and apoptosis in retinal cells and exerted beneficial effects on the blood–retinal barrier integrity in ZDF rat retinas.
ISSN:1462-8902
1463-1326
DOI:10.1111/j.1463-1326.2011.01548.x