Dipeptidyl peptidase-IV inhibition prevents blood-retinal barrier breakdown, inflammation and neuronal cell death in the retina of type 1 diabetic rats.
Diabetic retinopathy, a leading cause of vision loss in working-age population, is often associated with inflammation and apoptosis. We have previously reported that sitagliptin, a DPP-IV inhibitor, exerts beneficial effects in the retina of type 2 diabetic animals. The present study aimed to evaluate whether sitagliptin can exert protective effects in the retina of type 1 diabetic animals by a mechanism independent of insulin secretion and glycemia normalization. Streptozotocin-induced diabetic rats were treated orally with sitagliptin (5mg/kg/day) for the last two weeks of 4 weeks of diabetes. Sitagliptin treatment did not change the weight and glucose, HbA1c or insulin levels. However, it prevented the diabetes-induced increase in DPP-IV/CD26 activity and levels in serum and retina. Sitagliptin also prevented the increase in blood-retinal barrier (BRB) permeability and inhibited the changes in immunoreactivity and endothelial subcellular distribution of occludin, claudin-5 and ZO-1 proteins induced by diabetes. Furthermore, sitagliptin decreased the retinal inflammatory state and neuronal apoptosis. Sitagliptin inhibited the BRB breakdown in a type 1 diabetic animal model, by a mechanism independent of normalization of glycemia, by preventing changes in tight junctions (TJs) organization. Sitagliptin also exerted protective effects against inflammation and pro-apoptotic state in the retina of diabetic rats. Altogether, these results suggest that sitagliptin might be envisaged to be used to prevent or delay some of the alterations associated with the development of diabetic retinopathy.
Laboratory of Pharmacology and Experimental Therapeutics, IBILI - Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Portugal.
Andreia
A
Gonçalves
Laboratory of Pharmacology and Experimental Therapeutics, IBILI - Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Portugal.
Catarina
C
Marques
Centre for Neuroscience and Cell Biology, University of Coimbra, Portugal.
Ermelindo
E
Leal
Laboratory of Pharmacology and Experimental Therapeutics, IBILI - Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Portugal.
Carlos F
CF
Ribeiro
Laboratory of Pharmacology and Experimental Therapeutics, IBILI - Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Portugal.
Flávio
F
Reis
Centre of Ophthalmology and Vision Sciences, IBILI, Faculty of Medicine, University of Coimbra, Portugal; AIBILI, University of Coimbra, Portugal.
António F
AF
Ambrósio
Laboratory of Pharmacology and Experimental Therapeutics, IBILI - Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Portugal. Electronic address: rcfernandes@fmed.uc.pt.
Rosa
R
Fernandes
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D001813:Blood-Retinal Barrier / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D016923:Cell Death; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology
D015415:Biomarkers; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate
Blood–retinal barrier; Cell death; Diabetic retinopathy; Inflammation; Sitagliptin; Type 1 diabetes