Abstract

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 · kg body wt⁻¹ · day⁻¹) until 50 weeks of age and compared with insulin treatment. Although similar HbA_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^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 Bcl-2 and p27^Kip1 protein levels. Besides glucose-lowering action, pioglitazone ameliorates diabetic nephropathy via cell cycle–dependent mechanisms.