Advancing Diabetic Retinopathy Research: Analysis of the Neurovascular Unit in Zebrafish

Abstract

Diabetic retinopathy is one of the most important microvascular complications associated with diabetes mellitus, and a leading cause of vision loss or blindness worldwide. Hyperglycaemic conditions disrupt microvascular integrity at the level of the neurovascular unit. In recent years, zebrafish (Danio rerio) have come into focus as a model organism for various metabolic diseases such as diabetes. In both mammals and vertebrates, the anatomy and the function of the retina and the neurovascular unit have been highly conserved. In this review, we focus on the advances that have been made through studying pathologies associated with retinopathy in zebrafish models of diabetes. We discuss the different cell types that form the neurovascular unit, their role in diabetic retinopathy and how to study them in zebrafish. We then present new insights gained through zebrafish studies. The advantages of using zebrafish for diabetic retinopathy are summarised, including the fact that the zebrafish has, so far, provided the only animal model in which hyperglycaemia-induced retinal angiogenesis can be observed. Based on currently available data, we propose potential investigations that could advance the field further.

Differential Responses of Neural Retina Progenitor Populations to Chronic Hyperglycemia

“…Although we did not see immune cell infiltration into the retina, this does not rule out an enhanced inflammatory state. Accumulating perivascular microglia release cytokines that can penetrate into the retina [21], and retinal neurons themselves, including photoreceptors, can secrete pro-inflammatory factors [7]. The elevated expression of the inflammatory mediator NF-KB was detected by Western blot in retinal homogenates from zebrafish following four weeks of alternating glucose immersion, but the cell of origin was not identified [24].…”

“…Adult zebrafish models of diabetic retinopathy have been scarce but have highlighted similarities between mammals and zebrafish [21]. Previous studies addressing the effects of hyperglycemic conditions on the neural retina have mostly relied upon immersion in glucose solutions, which can only be maintained for several weeks.…”

Diabetic Retinopathy: Role of Neurodegeneration and Therapeutic Perspectives

“…Zebrafish (Danio rerio), a freshwater fish native to South Asia, is a popular aquarium fish widely used in preclinical drug development. Zebrafish is used as DR model given that it has a retinal structure similar to that of the human eye including the main components of the NVU 66 . In contrast to rodents, zebrafish have a cone-dominated retina and develop neovascularization.…”

“…Zebrafish is used as DR model given that it has a retinal structure similar to that of the human eye including the main components of the NVU. 66 In contrast to rodents, zebrafish have a cone-dominated retina and develop neovascularization. These characteristics, combined with their short lifespan, rapid growth, and ability to breed in large numbers, make them ideal for high-throughput screening, genetic screening, and significantly shorter experimental times.…”

“…These characteristics, combined with their short lifespan, rapid growth, and ability to breed in large numbers, make them ideal for high-throughput screening, genetic screening, and significantly shorter experimental times. 49 However, the lack of similarity in retinal vascular structure between zebrafish and humans, difficult handling due to tiny size, and a lack of reagents for molecular studies are factors responsible for the limited use of zebrafish as a screening model for DR. 58 Regarding neurodegeneration induced by diabetes, there are conflicting results that could be attributed to the different methods used to induce diabetes (immersion-induced hyperglycemia, STZ injection, or genetic models), 66 as well to the regenerative capabilities of the zebrafish retina. 67 In this regard, it should be noted that, unlike mammals, zebrafish are able to regenerate the damaged neuroretina.…”