An aldose reductase inhibitor prevents glucose-induced increase in transforming growth factor-beta and protein kinase C activity in cultured mesangial cells.
We investigated the effect of inhibition of a polyol pathway on the glucose-induced increase in transforming growth factor-beta (TGF-beta) production and activity of protein kinase C (PKC) in cultured human mesangial cells (MCs). The exposure of MCs to 33 mmol/l glucose resulted in an increase in TGFbeta production, measured by ELISA, compared with 5 mmol/l glucose. The glucose-induced increase in TGF-beta was prevented by concomitant incubation with epalrestat, an aldose reductase inhibitor (ARI), in a dose-dependent manner at a concentration of more than 10(-6) mol/l. Moreover, the glucose-induced enhancement of PKC activity in the membrane fraction of MCs was also abolished by epalrestat. The addition of epalrestat to MCs cultured with 5 mmol/l glucose showed no demonstrable effects on TGF-beta production and PKC activity. These results provide direct evidence for linkages between derangements in polyol pathway and glucose-induced overproduction of TGF-beta and enhancement of PKC activity in MCs. Accordingly, the effect of an ARI on these metabolic abnormalities in MCs may justify its clinical application for treatment of diabetic nephropathy.
Ishii
H
H
Second Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan.
Tada
H
H
Isogai
S
S
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism*; D012236:Rhodanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D053778:Thiazolidines; D016212:Transforming Growth Factor beta / Q000187:drug effects* / Q000378:metabolism
D004791:Enzyme Inhibitors; D053778:Thiazolidines; D016212:Transforming Growth Factor beta; C038131:epalrestat; D012236:Rhodanine; D000449:Aldehyde Reductase; D011493:Protein Kinase C; D005947:Glucose