Ocular findings in Zucker Diabetic Fatty rats emphasize the key role of neuroglia degeneration in diabetic retinopathy pathophysiology

Diabetes mellitus is a leading cause of acquired vision loss and one of the world’s fastest growing chronic diseases. Diabetic retinopathy (DR), a specific complication of chronic hyperglycemia, is the leading cause of acquired vision loss worldwide in middle-aged and therefore economically active people that also increases the medical and economic burden on the society (Klein, 2007). The natural history of DR has been divided into two clinical stages based on the proliferative status of the retinal vasculature: an early, non-proliferative stage and an advanced, proliferative or neovascular stage. Although DR has been regarded as a vascular disorder for many years, neuroglial abnormalities have also been recognized and are still being explored to determine their clinical significance. A lot of important information or clues on the development of DR can be obtained from human studies; however, the complete mechanisms of DR development have not yet been elucidated. In this sense, diabetic rat models are playing key roles in elucidating the pathogenesis of human diabetes and its complications, such as nephropathy, retinopathy, and neuropathy. Although spontaneous diabetic rat models are well characterized in terms of retina-choroid vascular modifications, changes in retinal cells (neurons and glia) associated with hyperglycemia have not been studied in detail on most available models (Lai and Lo, 2013; Olivares et al., 2017). Early structural gliotic reactions were initially described in pharmacologically induced rat models of diabetes (Rungger-Brändle et al., 2000). Recently, neuroglial morphologic degenerative changes have been described in spontaneous diabetic Zucker Diabetic Fatty (ZDF) rats prior to changes in vasculature appearance (Fernandez-Bueno et al., 2017). The ocular findings observed in animal models of diabetes, such as the ZDF rats, emphasize that DR is not, at least initially, a primary vascular disorder and that prolonged damage to the neural and glial components of the retina plays a key role in the development of the disease. As a model of human disease, the rat offers some advantages over other species. Rats are the most widely used animals in medical research, because rat and human physiology are very similar. The size of the animal enhances its use as a disease model, and anatomical and physiological similarity of important organs allows extrapolation of how the organ responds to an experimental lesion and the effects of drug administration. Furthermore, 90% of rat genes have orthologs in the human genome (Mullins and Mullins, 2004). The use of rats as an experimental model in ophthalmology is very common due to multiple advantages, such as a relatively large eyeball, which allows to carry out functional, morphological and molecular analyses. Rat models of diabetes resemble human pathophysiology in important ways, including the ability of external agents (e.g., diet, stress and toxins) to modify the disease. Rodents are the most commonly used models for studying DR. However, rodents do not have a fovea and some manifestations of DR, such as diabetic macular edema, cannot be reproduced in rodent models. Dogs develop similar morphological retinal lesions as those seen in humans, and pigs and zebrafish have similar vasculature and retinal structures to humans (Olivares et al., 2017). To have a better understanding of the development of DR at the molecular and cellular levels, a variety of diabetic rat models have been studied. The most useful diabetic rat models are those that spontaneously develop the disease. There are six genetic rat models of DR: biobreeding (BB), Otsuka long-evans Tokushima fatty (OLETF), ZDF, Wistar Bonn/Kobori (WBN/Kob), Goto-Kakizaki (GK), and spontaneously diabetic Torii (SDT). The BB, OLETF, and ZDF are monogenic models of DR with independent mutations that perturb different nodes of the DR disease pathway. The WBN/Kob, GK, and SDT models, in contrast, are polygenic models. Although ocular vessel degeneration is profoundly characterized in these models, few examinations have studied the retina neuroglia modifications associated with hyperglycemia in detail.