Troglitazone Inhibits Isolated Cell Proliferation, and Induces Apoptosis in Isolated Rat Mesangial Cells

Abstract

Background/Aims: Troglitazone is one of thiazolidinedione derivatives as a high affinity ligand for peroxisome proliferator-activated receptor-gamma (PPAR-γ). 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-γ 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-γ 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.

Ciglitazone Induces Caspase-Independent Apoptosis through Down-Regulation of XIAP and Survivin in Human Glioma Cells

“…Whether PPARc agonists induce cell death through a Bax-dependent mechanism remains unclear. Bax expression is not altered by troglitazone, a PPARc agonist, in different cell types [8,55,56], whereas 15d-PGJ 2 causes an increase in Bax expression [38,57,58]. In a previous study, we observed in osteoblasts that ciglitazone increases Bax expression [59], suggesting a Bax-dependent cell death.…”

PPARs in Diseases: Control Mechanisms of Inflammation

“…During inflammation or high glucose stimulation, mesangial cells undergo transformation to a proliferative myofibroblastlike phenotype, characterized by increased expression of ECM proteins, α-SMA, pro-inflammatory cytokines, prostaglandins and oxidants [116,117]. The activation of PPARγ with troglitazone and 15d-PGJ 2 inhibits the proliferation of cultured rat mesangial cells, reduces their production of α-SMA, induces apoptosis and modulates differentiation [118,119] (Table 1). MCP-1 production is thought to play a role in the increase of inflammation in the kidney, since it participates in the recruitment of immune cells.…”

Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule

“…Secondly, the increased levels of Bcl-2 may represent the displaced Bcl-2 protein that may have a longer half-life within the cell. Indeed, others have reported a similar increase in Bcl-2 during troglitazone (high-affinity ligand for peroxisome proliferators-activated receptor-gamma) -mediated apoptosis [30]. …”