Upregulation of glutamate-aspartate transporter by glial cell line-derived neurotrophic factor ameliorates cell apoptosis in neural retina in streptozotocin-induced diabetic rats

CNS Neurosci Ther. 2013 Dec;19(12):945-53. doi: 10.1111/cns.12150. Epub 2013 Jul 22.

Abstract

Aims: Dysfunction of glutamate uptake, largely mediated by the glutamate-aspartate transporter (GLAST), may lead to retinal cell apoptosis in diabetic retinopathy. The aim of this study is to examine how cell apoptosis and the expression level of GLAST in neural retina of a diabetic rat model are changed and whether the neuroretinal apoptosis could be ameliorated by the administration of glial cell line-derived neurotrophic factor (GDNF).

Methods: Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) in Sprague-Dawley rats. GLAST protein expression levels were determined by Western blotting, whereas apoptosis of retinal neurons was evaluated by TUNEL staining. To assess the role of GDNF in ameliorating the STZ-induced retinal changes, GDNF/GDNF with siRNA directed against GLAST was injected into the vitreous after STZ injection.

Results: In rat retinas 4 weeks after the onset of STZ-induced diabetes, TUNEL-positive cells were significantly increased, whereas GLAST levels were significantly reduced. Intraocular administration of GDNF at the early stage of diabetes remarkably increased the GLAST levels and decreased TUNEL-positive signals in the retinas. These effects of GDNF were largely abolished by coadministration of GLAST siRNA.

Conclusions: GDNF, administrated at the early stage of diabetes, could rescue retinal cells from neurodegeneration by upregulating the expression of GLAST.

Keywords: Apoptosis; Diabetic retinopathy; Glial cell line-derived neurotrophic factor; Glutamate-aspartate transporter; Streptozotocin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / pathology
  • Disease Models, Animal
  • Excitatory Amino Acid Transporter 1 / metabolism*
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacology
  • Glial Cell Line-Derived Neurotrophic Factor / therapeutic use*
  • In Situ Nick-End Labeling
  • Male
  • Neurons / drug effects*
  • Neurons / metabolism
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Retina / pathology*
  • Up-Regulation / drug effects*

Substances

  • Excitatory Amino Acid Transporter 1
  • Glial Cell Line-Derived Neurotrophic Factor
  • RNA, Small Interfering
  • Slc1a3 protein, rat