The role of polyol pathway in glucose-induced apoptosis of cultured retinal pericytes.
The pathogenesis of pericyte loss, an initial deficit in the early stage of diabetic retinopathy, remains unclear. Recent studies have suggested that polyol pathway hyperactivity and apoptosis may be involved in pericyte loss. The mechanisms of the glucose-induced apoptosis in retinal pericytes were investigated to evaluate the pathogenesis of diabetic retinopathy. Under the 20 mM glucose condition, intracellular calcium concentrations and caspase-3 activities were significantly increased, and reduced glutathione (GSH) contents were significantly decreased compared with those under the 5.5 mM glucose condition. These abnormalities were all significantly prevented by an aldose reductase inhibitor, SNK-860. Glucose-induced apoptosis was partially but significantly prevented by SNK-860, an inhibitor of calcium-dependent cysteine protease, calpain, or GSH supplementation, and completely normalized by a caspase-3 inhibitor. These observations suggest that glucose-induced apoptosis in retinal pericytes, as one of the pathogenic factors of diabetic retinopathy, would be mediated through an aldose reductase-sensitive pathway including calcium-calpain cascade and increased oxidative stress, and that caspase-3 would be located furthest downstream of these apoptotic signals.
Miwa
Kazuma
K
The Third Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Japan.
Nakamura
Jiro
J
Hamada
Yoji
Y
Naruse
Keiko
K
Nakashima
Eitaro
E
Kato
Koichi
K
Kasuya
Yasuhide
Y
Yasuda
Yutaka
Y
Kamiya
Hideki
H
Hotta
Nigishi
N
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002417:Cattle; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D005947:Glucose / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D020286:Pericytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011108:Polymers / Q000378:metabolism*; D012171:Retinal Vessels
D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D011108:Polymers; C024617:polyol; D000449:Aldehyde Reductase; D020170:Caspase 1; D005978:Glutathione; D005947:Glucose; D002118:Calcium