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Thiazolidinediones Ameliorate Diabetic Nephropathy via Cell Cycle–Dependent Mechanisms

Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Okayama, Japan

Address correspondence and reprint requests to Jun Wada, MD, PhD, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail: junwada{at}md.okayama-u.ac.jp

Abbreviations: CDK, cyclin-dependent kinase; DMEM, Dulbecco’s modified Eagle’s medium; ERK, extracellular signal–regulated kinase; MAPK, mitogen-activated protein kinase; MPC, mouse podocyte cell; PAS, periodic acid-Schiff; PPAR, peroxisome proliferator–activated receptor; pRb, retinoblastoma protein; TGF, transforming growth factor; TZD, thiozolidinedione

Thiazolidinediones are ligands for peroxisome proliferator–activated receptor (PPAR)-, 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- 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.

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