Nerve growth factor prevents both neuroretinal programmed cell death and capillary pathology in experimental diabetes.
BACKGROUND
Chronic diabetes causes structural changes in the retinal capillaries of nearly all patients with a disease duration of more than 15 years. Acellular occluded vessels cause hypoxia, which stimulates sight-threatening abnormal angiogenesis in 50% of all type I diabetic patients. The mechanism by which diabetes produces acellular retinal capillaries is unknown.


METHODS
In this study, evidence of programmed cell death (PCD) was sought in the retinas of early diabetic rats, and the effect of nerve growth factor (NGF) on PCD and capillary morphology was evaluated.


RESULTS
Diabetes induced PCD primarily in retinal ganglion cells (RGC) and Muller cells. This was associated with a transdifferentiation of Muller cells into an injury-associated glial fibrillary acidic protein (GFAP)-expressing phenotype, and an up-regulation of the low-affinity NGF receptor p75NGFR on both RGC and Muller cells. NGF treatment of diabetic rats prevented both early PCD in RGC and Muller cells, and the development of pericyte loss and acellular occluded capillaries.


CONCLUSIONS
These data provide new insight into the mechanism of diabetic retinal vascular damage, and suggest that NGF or other neurotrophic factors may have potential as therapeutic agents for the prevention of human diabetic retinopathy.
Hammes
H P
HP
III. Medizinische Klinik und Poliklinik, Zentrum fur Innere Medizin, Justus-Liebig-Universitat, Giessen, Germany.
Federoff
H J
HJ
Brownlee
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006651:Histocytochemistry; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology*; D015854:Up-Regulation
D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor