The effect of aminoguanidine and tolrestat on glucose toxicity in bovine retinal capillary pericytes.
Cultured bovine retinal capillary pericytes (BRP) were used to investigate the effect of an aldose reductase inhibitor, tolrestat, and an inhibitor of advanced glycation end products (AGE) formation, aminoguanidine, on glucose toxicity. Glucose at high concentration reduced the replicative activity of pericytes in a dose-dependent manner. Tolrestat completely inhibited the production of sorbitol in cells exposed to a high concentration of glucose but failed to protect the cells from glucose toxicity. These results suggest that sorbitol accumulation in cells is probably not the major mechanism for glucose toxicity. In contrast, the addition of aminoguanidine at 10 mM concentration to the culture media protected pericytes from glucose toxicity. The degree of protected pericytes from glucose toxicity. The degree of protection was dose-dependent and evident at aminoguanidine concentration as low as 1 mM. The drug was only slightly toxic to BRP but induced morphological changes in pericytes with the loss of cellular processes and decreased cell spreading. This may suggest some action of aminoguanidine on the pericyte cytoskeleton. High concentration of glucose significantly increased the level of early glycation but not fluorescent AGE formation on BRP proteins. This was inhibited by the addition of aminoguanidine suggesting that glycation of cellular/membrane proteins and other mechanisms may play an important role in the toxic action of high glucose levels in cultured pericytes.
Chibber
R
R
Diabetic Retinopathy Unit, Royal Postgraduate Medical School, London.
Molinatti
P A
PA
Wong
J S
JS
Mirlees
D
D
Kohner
E M
EM
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002196:Capillaries / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism / Q000633:toxicity*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D012171:Retinal Vessels / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013997:Time Factors
D003470:Culture Media; D017127:Glycation End Products, Advanced; D006146:Guanidines; D009281:Naphthalenes; C040550:tolrestat; D013012:Sorbitol; D000449:Aldehyde Reductase; D005947:Glucose; C004479:pimagedine