Thiazolidinediones ameliorate diabetic nephropathy via cell cycle-dependent mechanisms
Thiazolidinediones ameliorate diabetic nephropathy via cell cycle-dependent mechanisms
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DOI：
10.2337/db05-1285
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发表时间：
2006-06-01
期刊：
影响因子：
7.7
通讯作者：
Makino, Hirofumi
中科院分区：
文献类型：
--
作者：
Okada, Tatsuo;Wada, Jun;Makino, Hirofumi
噻唑烷二酮类化合物是过氧化物酶体增殖物激活受体激活受体(PPAR)-γ的配体，广泛用于2型糖尿病患者的胰岛素增敏，参与细胞凋亡、细胞增殖和细胞周期调节。在这里，我们研究了噻唑烷二酮类药物对糖尿病肾病的标志--G1期细胞周期停滞的影响。用8周龄雄性大冢Long-Evans Tokushima肥胖大鼠，给予吡格列酮1 mg kg体重(wt(-1)(.)天(-1))，直到50周龄，并与胰岛素治疗进行比较。虽然两组的HbA(1c)水平相似，但与胰岛素治疗组相比，吡格列酮显著抑制肾小球肥大和系膜基质扩张，并减少尿白蛋白排泄。此外，吡格列酮显著减少肾小球p27(Kip1)阳性细胞的数量。由于PPAR-γ在肾小球和培养细胞的足细胞中有明显的表达，条件永生化的小鼠足细胞在添加吡格列酮的5.5和25 mmol/L葡萄糖中培养。吡格列酮抑制[H-3]胸腺嘧啶核苷和[H-3]脯氨酸掺入所显示的细胞肥大，并逆转高糖诱导的G1期细胞周期停滞，即G0/G1期增加，S和G2期减少。吡格列酮可抑制高糖诱导的p44/42丝裂原活化蛋白激酶的磷酸化，降低Bcl2和P27(Kip1)蛋白水平。除了降糖作用外，吡格列酮还通过细胞周期依赖机制改善糖尿病肾病。
Thiazolidinediones are ligands for peroxisome proliferator-activated receptor-activated receptor (PPAR)-gamma, 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-gamma 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 [H-3]thymidine and [H-3]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.