Photoreceptor Degeneration Accompanies Vascular Changes in a Zebrafish Model of Diabetic Retinopathy

Abstract

PURPOSE. Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness worldwide in the working-age population, and the incidence is rising. Until now it has been difficult to define initiating events and disease progression at the molecular level, as available diabetic rodent models do not present the full spectrum of neural and vascular pathologies. Zebrafish harboring a homozygous mutation in the pancreatic transcription factor pdx1 were previously shown to display a diabetic phenotype from larval stages through adulthood. In this study, pdx1 mutants were examined for retinal vascular and neuronal pathology to demonstrate suitability of these fish for modeling DR. METHODS.Vessel morphology was examined in pdx1 mutant and control fish expressing the fli1a:EGFP transgene. We further characterized vascular and retinal phenotypes in mutants and controls using immunohistochemistry, histology, and electron microscopy. Retinal function was assessed using electroretinography. RESULTS.Pdx1 mutants exhibit clear vascular phenotypes at 2 months of age, and disease progression, including arterial vasculopenia, capillary tortuosity, and hypersprouting, could be detected at stages extending over more than 1 year. Neural-retinal pathologies are consistent with photoreceptor dysfunction and loss, but do not progress to blindness. CONCLUSIONS.This study highlights pdx1 mutant zebrafish as a valuable complement to rodent and other mammalian models of DR, in particular for research into the mechanistic interplay of diabetes with vascular and neuroretinal disease. They are furthermore suited for molecular studies to identify new targets for treatment of early as well as late DR.

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

“…These findings are exciting from multiple perspectives. The confirmation that two different pdx1 mutants by two independent groups produce a phenotype resembling DR in zebrafish establishes this zebrafish mutant line as a reliable and reproducible model for further research into the mechanisms associated with DR, particularly retinal angiogenesis in adults [53,55]. Furthermore, the homozygous pdx1 mutant is the first animal model to show retinal angiogenesis under hyperglycaemia.…”

“…ZO-1 is a molecule that is integral to tight junctions which are responsible for connecting endothelial cells and regulating permeability in vessels. Furthermore, GLUT1 expression was largely absent in mutants compared to wildtype controls [53]. Changes in GLUT1 expression have also been reported in DR patients and mouse models [54].…”

Neurodegeneration, Neuroprotection and Regeneration in the Zebrafish Retina

“…Hyperglycemia also significantly reduced the amplitude of the d-wave, which is thought to be derived from the OFF-bipolar cells. Recently the pancreatic transcription factor mutant, pdx1 −/− zebrafish was shown to have a diabetic phenotype [ 146 ], which exhibits functional deficits including a significant reduction in the b-wave amplitude accompanied by retinal vascular abnormalities and degeneration of rods and RGB cones [ 147 ]. The recent data suggest that pdx1 −/− zebrafish may represent a useful new model of retinal complications due to diabetes that include some of the neurodegenerative features leading to loss of visual function.…”

Animal models of diabetic retinopathy

“…Recently there has been a growing interest for the use of non-human primates for drug discovery in DR, although previously non-human primates have demonstrated resistance to development of PDR (43,44). Zebrafish, surprisingly, have similar eye structure to humans and are growing in use for their efficient short life span and minimal cost (35,(45)(46)(47)(48). Although there is a wide range of animal models to study each stage of DR, there is no single model that fully encompasses the entire DR pathogenesis of the human eye.…”