Effect of Candesartan on the development of diabetic retinopathy in a diabetes mouse model

Abstract

Purpose: Angiotensin II (Ang II) is thought to be a pro-inflammatory factor released in response to hyperglycemia and modulates inflammation as well as the expression of vascular endothelial growth factor (VEGF) in the retina through activation of Ang II type 1 (AT1) receptor. This study is aimed to investigate the effect of blockade of Ang II by Candesartan, an AT1 receptor blocker, on the functional and morphological abnormalities of the neurovascular unit in experimental diabetic retinopathy.

Methods: Candesartan (0.1ug/g/day or 1.0ug/g/day in drinking water) was given to Ins2^Akita/+ mice, a spontaneous type I diabetes model. Vehicle-treated (0.1% DMSO) Ins2^Akita/+ mice and their wildtype littermates, Ins2^+/+ mice, were used as controls. Blood glucose, blood pressure and body weight were monitored weekly. Retinal function was assessed by scotopic ERG. After 8 or 22 weeks of hyperglycemia with or without Candesartan treatment, vascular pathologic alterations including quantitation of VEGF expression, leukostasis and vascular permeability in the retina were evaluated. Astrocyte morphology was examined by glial fibrillary acidic protein (GFAP) immunoreactivity. Statistical analyses were performed using One-way ANOVA followed by Bonferroni-Dunn test.

Results: Vehicle-treated Ins2^Akita/+ mice (n=8) showed the following changes (p<0.05) when compared with age-matched wildtype littermates (n=8): elevated blood glucose level, reduced body weight, decreased b-wave amplitude in scotopic ERG, increased leukostasis and expression of VEGF, vascular leakage, and atrophy of astrocyte. Candesartan-treated Ins2^Akita/+ mice (n=8 in either dosage) showed decreased blood pressure (p<0.01) and exhibited normalization (p<0.05) of increased leukostasis, up-regulation of VEGF and vascular leakage as well as amelioration (p<0.05) of retinal dysfunction and astrocyte atrophy when compared with vehicle-treated Ins2^Akita/+ mice, but had no changes in the overall blood glucose level and body weight.

Conclusions: Hyperglycemia induced retinal dysfunction, vascular leakage, inflammation, and astrocyte atrophy. These abnormalities were attenuated by the treatment with Candesartan, suggesting that blockade of AT1-receptor has a beneficial effect on maintenance of retinal function, vascular integrity and astrocyte survival within the neurovascular unit in experimental diabetes.