Histological evaluation of early diabetic neurodegenertion in Zucker Diabetic Fatty (ZDF) Rats

Abstract

Purpose: Literature data indicates that in diabetes retinal dysfunctions related to neural retinal alterations exist prior to clinically detectable vasculopathy, however, the histological background behind these functional deficits is largely unknown. Previously, a detailed description about the histology of the outer and inner retina was given in streptozocin (STZ) induced (type 1) diabetic rats, where neural retinal degeneration preceded apoptotic loss of cells. Here, we investigated the histopathology of the retina in early diabetes using Zucker Diabetic Fatty (ZDF) rats, a well-know model of type 2 diabetes.

Methods: The morphology, density and staining characteristics of the labeled cells were analyzed by immunohistochemistry after six months of diabetes, using cell-type specific antibodies.

Results: Glial reactivity was observed in all diabetic retinal specimens, manifested by strong GFAP upregulation. Marked outer segment degeneration was detected in rods and in the majority of M/L-cones, without an apparent decrease in the number of stained elements and without any major change in the expression of other photoreceptor specific markers like arrestin and transducin. An increase in the number of dual cones, coexpressing two photopigments was also visible. The immunoreactivity of parvalbumin (staining mostly AII amacrine cells) was markedly decreased and we detected a change in the number of PKC-α labeled amacrine and displaced amacrine cells. In contrast to these, most other markers used (including calretinin, recoverin, tyrosin hydroxylase, anti-Brn-3a, NeuN and calbindin) did not show any major alterations in the intensity of immunoreactivity or in the number of stained elements.

Conclusions: Overall, the retina of ZDF rats shows a surprising similarity to STZ induced type 1 diabetic rats, indicating that most of the changes are consequences of the high glucose levels while the lack of insulin does not play a decisive role in the development of histological alterations. The presence of early retinal degeneration raises the possibility that neuroprotective therapy in diabetic patients should be beneficial even prior to vasculopathy or overt loss of cells.