Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals

Abstract

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and one of the major causes of blindness worldwide. The pathogenesis of DR has been investigated using several animal models of diabetes. These models have been generated by pharmacological induction, feeding a galactose diet, and spontaneously by selective inbreeding or genetic modification. Among the available animal models, rodents have been studied most extensively owing to their short generation time and the inherited hyperglycemia and/or obesity that affect certain strains. In particular, mice have proven useful for studying DR and evaluating novel therapies because of their amenability to genetic manipulation. Mouse models suitable for replicating the early, non-proliferative stages of the retinopathy have been characterized, but no animal model has yet been found to demonstrate all of the vascular and neural complications that are associated with the advanced, proliferative stages of DR that occur in humans. In this review, we summarize commonly used animal models of DR, and briefly outline the in vivo imaging techniques used for characterization of DR in these models. Through highlighting the ocular pathological findings, clinical implications, advantages and disadvantages of these models, we provide essential information for planning experimental studies of DR that will lead to new strategies for its prevention and treatment.

Fig. 1.

Clinical features of DR. Fundus photographs of human patients showing (A) early non-proliferative diabetic retinopathy (NPDR) and (B) proliferative diabetic retinopathy (PDR).

Fig. 2.

Flow diagram showing the major key factors involved in the pathogenesis of DR and the clinical symptoms evident at different stages of DR. DR is a multifactorial disease involving several pathological mechanisms, including increased oxidative stress, inflammation, the polyol pathway leading to sorbitol accumulation, production of advanced glycation end products (AGEs) and activation of the protein kinase C (PKC) pathway. These pathways can in turn activate the production of cytokines and many vasoactive factors, such as vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF), which are vital in mediating the structural and functional changes of DR. Clinically significant diabetic macular edema (DME) can occur in the late stages of DR with non-proliferative or proliferative retinopathy and is the most common cause of vision loss.

Fig. 3.

Fundus fluorescein angiography (FFA) images show the comparison between normal B6 (pigmented) and Swiss albino (non-pigmented) mice. Normal (A) B6 (pigmented) and (B) Swiss albino (non-pigmented) mice. FFA cannot be used in albino mice owing to the absence of pigment, which produces severe glare.

Fig. 4.

Retinal vascular caliber measurement. The measurement of retinal vessel caliber in human (A,B) and mouse (C,D) with fundus imaging, using semi-automated computer-based quantitative program (SIVA). The white arrow indicates the artery, the black arrow indicates the vein and an asterisk (*) shows the optic nerve head.

Fig. 5.

Comparison of retinal fundus, FFA and histology of Kimba, Akimba and Akita mice. Fundus, FFA and retinal histology of Kimba (A–C), Akimba (D–F) and Akita (G–I) mice (courtesy of Lions Eye Institute, Perth, Australia). FFA shows the differences in retinal vasculature between Kimba (B), Akimba (E) and Akita (H) mice. Kimba (B) and Akimba (E) mice have foci of fluorescein leakages (arrows). Akita (H) mice have sharply defined retinal vessels and retinal capillary network with vessels radiating from the optic nerve head. Light micrographs of paraffin-embedded eyes of Kimba (C), Akimba (F) and Akita (I) mouse eyes show retinal histology. The sections were stained with H&E. Arrows in C and F point to breaks in the RPE cells of Kimba and Akimba mouse eyes, whereas arrows in (I) point to intact RPE cells in Akita eyes. Ganglion cell layer (GCL); inner nuclear layer (INL); inner plexiform layer (IPL); outer plexiform layer (OPL); and outer nuclear layer (ONL).