Glial cell line–derived neurotrophic factor (GDNF) belongs to the neurotrophic factor family. GDNF functions are not restricted to neurons but are also implicated in glial cell development (1). We observed high expression levels of GDNF receptor family α-component 2 (GFRα2) in epiretinal membranes (ERMs) in proliferative diabetic retinopathy (PDR), indicating the involvement of GFRα2 in ERM formation in PDR (2). Here, we examined the vitreous of patients with PDR for the presence of GDNF.
We assayed GDNF levels in vitreous and serum samples from 75 consecutive patients with PDR (54 patients) and macular hole (nondiabetic control subjects, 21 patients) who underwent vitrectomy. PDR was classified as active (33 patients) when there were perfused, multibranching iridic or preretinal capillaries and as quiescent (21 patients) when only large vessel or fibrosis was present. Informed consent was obtained from each patient. Undiluted vitreous samples were obtained during the vitrectomy before intraocular infusion. Enzyme-linked immunosorbent assay was performed to determine GDNF level using a commercially available immunoassay kit (Promega, Madison, WI). Mann-Whitney U test was used to compare GDNF levels.
GDNF was undetectable in all the serum samples examined. Intravitreous GDNF level was significantly higher in the PDR patients (means ± SD: 156.1 ± 221.0 pg/ml) than in the control subjects (26.5 ± 53.2 pg/ml) (P = 0.0042). Intravitreous GDNF level was significantly higher in active PDR (206.0 ± 250.7 pg/ml) than in quiescent PDR (77.7 ± 135.5 pg/ml) (P = 0.0388).
Glial cells are one of the main components of ERMs. Our previous study (2) showed that GFRα2 mRNA expression level is significantly higher in PDR ERMs than in idiopathic ERMs, and this high expression level is specific for GFRα2 among neurotrophin receptors. GFRα2 protein is detected in the glial component of PDR ERMs. These results suggest that GDNF is involved in the formation of the glial cell component of PDR ERMs. Results of the present study support this suggestion. Because GDNF increases basic fibroblast growth factor (bFGF) production in Müller cells (3), released bFGF may stimulate endothelial proliferation.
In this study, GDNF was undetectable in the serum samples. It is suggested that the increased level of vitreous GDNF in PDR reflects intraocular GDNF production but not breakdown of the blood-retina barrier.
In conclusion, intravitreous GDNF level increased in PDR and was associated with the activity of PDR. These results suggest that GDNF is involved in the pathogenesis of PDR.