Troglitazone inhibits isolated cell proliferation, and induces apoptosis in isolated rat mesangial cells.
OBJECTIVE
Troglitazone is one of thiazolidinedione derivatives as a high affinity ligand for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The in vivo studies demonstrated that troglitazone ameliorated microalbuminuria. There have been few reports about direct effect of thiazolidinedione derivatives on mesangial cell function. We determined the effect of troglitazone on isolated rat mesangial cell proliferation.


METHODS
We determined PPAR-gamma mRNA expression in isolated rat mesangial cells. Chronic effects of 10(-6) to 10(-4) mol/l troglitazone on mesangial cell proliferation and mitogen-activated protein (MAP) kinase activity were also determined. The effects of troglitazone on apoptosis were investigated in rat mesangial cells.


RESULTS
Rat PPAR-gamma mRNA was detected in isolated rat mesangial cells. Living cell number, assessed by colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay, was significantly decreased with 10(-4) mol/l troglitazone. The addition of 10(-6) to 10(-4) mol/l troglitazone dose-dependently inhibited 5-bromo-2'-deoxyuridine (BrdU) uptake into isolated rat mesangial cells. The addition of 10(-4) and 10(-5) mol/l troglitazone significantly reduced MAP kinase activity. Troglitazone at the concentrations of 10(-6) to 10(-4) mol/l dose-dependently increased DNA fragmentation rates, indicating that troglitazone may cause apoptosis in rat mesangial cells. Bax and Bcl-xL proteins were not changed, although Bcl-2 proteins increased with troglitazone.


CONCLUSIONS
The present data demonstrated that troglitazone inhibits cell proliferation, and induces apoptosis in rat mesangial cells, raising a possibility that it directly affects renal function.
Tsuchiya
Takahumi
T
First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma, Japan.
Shimizu
Hiroyuki
H
Shimomura
Kenju
K
Mori
Masatomo
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D019950:Mitogen-Activated Protein Kinase 1; D001973:Bromodeoxyuridine; D000077288:Troglitazone