Predominant cone photoreceptor dysfunction in a hyperglycaemic model of non-proliferative diabetic retinopathy.
Approximately 2.5 million people worldwide are clinically blind because of diabetic retinopathy. In the non-proliferative stage, the pathophysiology of this ocular manifestation of diabetes presents as morphological and functional disruption of the retinal vasculature, and dysfunction of retinal neurons. However, it is uncertain whether the vascular and neuronal changes are interdependent or independent events. In addition, the identity of the retinal neurons that are most susceptible to the hyperglycaemia associated with diabetes is unclear. Here, we characterise a novel model of non-proliferative diabetic retinopathy in adult zebrafish, in which the zebrafish were subjected to oscillating hyperglycaemia for 30 days. Visual function is diminished in hyperglycaemic fish. Significantly, hyperglycaemia disrupts cone photoreceptor neurons the most, as evidenced by prominent morphological degeneration and dysfunctional cone-mediated electroretinograms. Disturbances in the morphological integrity of the blood-retinal barrier were also evident. However, we demonstrate that these early vascular changes are not sufficient to induce cone photoreceptor dysfunction, suggesting that the vascular and neuronal complications in diabetic retinopathy can arise independently. Current treatments for diabetic retinopathy target the vascular complications. Our data suggest that cone photoreceptor dysfunction is a clinical hallmark of diabetic retinopathy and that the debilitating blindness associated with diabetic retinopathy may be halted by neuroprotection of cones.
Alvarez
Yolanda
Y
UCD School of Biomolecular and Biomedical Sciences, UCD Conway Institute, University College Dublin, Belfield, Dublin D4, Ireland.
Chen
Kenneth
K
Reynolds
Alison L
AL
Waghorne
Nora
N
O'Connor
John J
JJ
Kennedy
Breandán N
BN
D000375:Aging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D001813:Blood-Retinal Barrier / Q000187:drug effects / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000150:complications* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004596:Electroretinography; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000150:complications* / Q000503:physiopathology*; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects / Q000473:pathology*; D012162:Retinal Degeneration / Q000150:complications / Q000503:physiopathology; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D015027:Zebrafish
D005947:Glucose