Age-dependent retinal capillary pericyte degeneration in galactose-fed dogs.
The galactose-fed beagle develops diabetes-like microvascular changes that are histologically and clinically similar in appearance to all stages of human diabetic retinopathy. This animal model is extremely useful for evaluating drugs for the treatment of diabetic retinopathy; however, the time required to develop the various retinal lesions (24-72 months for background to the proliferative stage) may be considered prohibitive. Retinal vascular changes begin with an initial degeneration of capillary pericytes, which has been linked to the aldose reductase catalyzed formation of galactitol. Because aldose reductase-linked sugar cataract formation is known to be age dependent, with the onset and severity of cataract higher in younger diabetic and galactose-fed animals, retinal capillary changes in the eyes of initially 2- versus 9-month-old beagles fed a diet containing 30% galactose were compared. Eyes were enucleated after 36 months of galactose feeding, the intact retinal capillaries were isolated by trypsin digestion, and defined retinal regions were evaluated by computer image analysis. Nicotinamide adenine dinucleotide phosphate-dependent reductase activity, using DL-glyceraldehyde and D-xylose as substrates, was also compared in the lenses and whole retinas of eyes from the 2- and 9-month-old beagles. Significantly (P<or=0.05) increased pericyte degeneration, expressed as either the number of pericytes/mm capillary length or the ratio of endothelial cells versus pericytes (E/P ratio) was observed in the retinas of the younger dogs. The number of microaneurysms per eye was also significantly increased in the younger dogs, but no difference in acellular capillary areas was observed. This correlates with a threefold higher level of reductase activity in the retinas of the 2-month-old dogs. Because retinal capillary pericyte destruction is age dependent similar to the formation of sugar cataracts, the use of younger dogs may shorten the time period required for evaluating the efficacy of drugs for diabetic retinopathy in this animal model.
Kador
Peter F
PF
Laboratory of Ocular Therapeutics, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. pkador@unmc.edu
Takahashi
Yukio
Y
Akagi
Yoshio
Y
Blessing
Karen
K
Randazzo
James
J
Wyman
Milton
M
D000375:Aging / Q000473:pathology*; D000818:Animals; D002196:Capillaries / Q000473:pathology; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D004285:Dogs; D005690:Galactose / Q000008:administration & dosage*; D005693:Galactosemias / Q000097:blood; D007908:Lens, Crystalline / Q000201:enzymology; D008297:Male; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D020286:Pericytes / Q000473:pathology*; D012162:Retinal Degeneration / Q000473:pathology*; D012171:Retinal Vessels / Q000473:pathology*
D004040:Dietary Carbohydrates; D009249:NADP; D009247:NADH, NADPH Oxidoreductases; D005690:Galactose