Studies on angiotensin II receptor antagonism in delaying diabetic retinopathy progression in a type 1 diabetic mouse model

Abstract

Diabetic retinopathy (DR) is one of the complications of diabetes mellitus, in which hyperglycemia-induced damages occur in the retina. It is the leading cause of preventable vision loss in working age populations and characterized by a series of retinal vascular compromises, including microaneurysms, exudative changes, ischemic changes, collateralization and venous beading, and proliferative changes, as well as neurodegeneration. Treatments rely almost exclusively on the managements of metabolic dysregulations until the severity of vascular damages needs laser surgery. New agents that block the action of vascular endothelial growth factor (VEGF) may also help in the late sight-threatening conditions. Angiotensin II (Ang II) has a central role in vascular homeostasis. Its concentration in the vitreous body was found to correlate with the severity of vascular lesions in diabetic patients, which highlighted the important role of intraocular Ang II in the pathogenesis of DR. More evidence suggested that Ang II might be involved in the hyperglycemia-induced upregulations of VEGF and other inflammatory factors, thus providing a therapeutic target in the treatments of DR. Therefore, the effects of Candesartan, an antagonist of Ang II, on diabetes-induced retinal lesions were investigated by using a mouse model of spontaneous diabetes.

The expressions of Ang II and VEGF in the retinas of diabetic mice after various durations of hyperglycemia were first examined. As VEGF is a potent mediator for vascular permeability, its associated abnormalities were also investigated. Upregulated expression of Ang II in diabetic retina was found in concomitant with overexpression of VEGF. Pharmacological inhibition of Ang II by Candesartan showed protective effect on VEGF overexpression. Moreover, VEGF-related retinal vascular lesions, including retinal vascular leakage, disruption of tight junctions, and vascular leukostasis, were ameliorated by the treatment of Candesartan, suggestive of beneficial effects in slowing the progression of DR. As VEGF is also known as a neuronal survival factor, cellular origin of pathogenic VEGF is crucial for the therapy. Muller cell-derived VEGF was found to be the major source of pathogenic VEGF in DR. Hence, primary cultured Muller cells were employed to study the effects of Ang II and its inhibition on Muller cell-derived VEGF. Challenge of Muller cells by Ang II upregulated VEGF expression in both transcriptional and translational level. Candesartan was found to reduce the upregulated VEGF, suggesting its beneficial effect in the modulation of pathogenic VEGF. As neural tissue and vasculature interconnect with each other in the inner retina, the effects of Candesartan on neurodegeneration were also investigated. Antagonism of Ang II attenuated diabetes-induced retinal dysfunction, glial atrophy, and neuroinflammation. The neuroprotective effects may be partly explained by the neurovascular interactions.

In conclusion, antagonism of Ang II by Candesartan ameliorated hyperglycemia-induced retinal vascular and neural abnormalities, possibly by modulating pathogenic VEGF pathway, indicating its beneficial role in delaying the progression of DR.