Thiazolidinediones ameliorate diabetic nephropathy via cell cycle--dependent mechanisms

The peroxisome proliferator--activated receptors (PPARs) PPAR-α, PPAR-δ, and PPAR-γ are a family of nuclear receptors that bind to fatty acid--derived ligands and activate the transcription of genes that govern various [...]
Thiazolidinediones are ligands for peroxisome proliferator-activated receptor (PPAR)-γ widely used as insulin sensitizer in type 2 diabetic patients and implicated in apoptosis, cell proliferation, and cell cycle regulation. Here, the effect of thiazolidinediones on G1-phase cell cycle arrest, the hallmark in diabetic nephropathy, was investigated. Eight-week-old male Otsuka Long-Evans Tokushima fatty rats were treated with pioglitazone (1 mg x kg body [wt.sup.-1] x [day.sup.1]) until 50 weeks o age and compared with insulin treatment. Although similar [HbA.sub.1c] levels were observed in both groups, pioglitazone significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion compared with the insulin-treated group. In addition, pioglitazone significantly reduced the number of glomerular [p27.sup.kip1]-positive cells. Because prominent expression of PPAR-γ was observed in podocytes in glomeruli and cultured cells, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 mmol/l D-glucose supplemented with pioglitazone. Pioglitazone inhibited cell hypertrophy revealed by ³H]thymidine and ³H]proline incorporation, and pioglitazone reversed high glucose-induced G1-phase cell cycle arrest, i.e., an increase in G0/G1 phase and decrease in S and G2 phases. Pioglitazone suppressed high glucose-induced phosphorylation of p44/42 mitogen-activated protein kinase and reduced Bc1-2 and [p27.sup.Kip1] protein levels. Besides glucose-lowering action, pioglitazone ameliorates diabetic nephropathy via cell cycle-dependent mechanisms. Diabetes 55:1666-1677, 2006