Diabetes-induced dysfunction of retinal Müller cells.
OBJECTIVE
This study tested the hypothesis that the function of the glutamate transporter in retinal Müller cells is compromised early in the course of diabetes by a mechanism involving oxidation. Dysfunction of this transporter, which removes glutamate from the extracellular space, may play a critical role in the disruption of glutamate homeostasis that occurs in the diabetic retina. Because glutamate is toxic to retinal neurons and is likely to exacerbate oxidative stress, elucidation of the mechanisms by which diabetes elevates the concentration of this amino acid may help to better understand the pathogenesis of diabetic retinopathy.


METHODS
Müller cells were freshly isolated from normal rats and those made diabetic by streptozotocin injection. The activity of the Müller cell glutamate transporter, which is electrogenic, was monitored via the perforated-patch configuration of the patch-clamp technique.


RESULTS
Four weeks after the onset of hyperglycemia, dysfunction of the Müller cell glutamate transporter was detected (P = .005). After 13 weeks of streptozotocin-induced diabetes, the activity of this transporter was decreased by 67% (P = .001). Consistent with oxidation causing this dysfunction, exposure to a disulfide-reducing agent rapidly restored the activity of this transporter in Müller cells from diabetic retinas.


CONCLUSIONS
Soon after the onset of experimental diabetes, the function of the glutamate transporter in Müller cells is decreased by a mechanism that is likely to involve oxidation. The demonstration that the activity of this transporter can be rapidly restored raises the possibility that targeting this molecule for therapeutic intervention may restore glutamate homeostasis and, thereby, ameliorate sight-threatening complications of diabetic retinopathy.
Puro
Donald G
DG
Departments of Ophthalmology and Visual Sciences and Physiology, University of Michigan, Ann Arbor, USA.
D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology; D004594:Electrophysiology; D018698:Glutamic Acid / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D018408:Patch-Clamp Techniques; D051381:Rats; D020318:Rats, Long-Evans
D027322:Amino Acid Transport System X-AG; D018698:Glutamic Acid