Rosiglitazone Inhibits Cell Proliferation by Inducing G1 Cell Cycle Arrest and Apoptosis in ADPKD Cyst-Lining Epithelia Cells
Rosiglitazone Inhibits Cell Proliferation by Inducing G1 Cell Cycle Arrest and Apoptosis in ADPKD Cyst-Lining Epithelia Cells
复制标题
罗格列酮通过诱导 ADPKD 囊肿内皮细胞 G1 细胞周期停滞和凋亡来抑制细胞增殖
DOI：
10.1111/j.1742-7843.2010.00539.x
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发表时间：
2010-06-01
影响因子：
3.1
通讯作者：
Mei, Changlin
中科院分区：
文献类型：
--
作者：
Liu, Yawei;Dai, Bing;Mei, Changlin
异常增殖是常染色体显性遗传性多囊肾病（ADPKD）的重要病理特征。许多抑制细胞增殖的药物已被证明能有效延缓ADPKD的病情进展。最近的证据表明，过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）配体通过抑制细胞生长和诱导各种癌细胞的细胞凋亡具有抗肿瘤作用。在本研究中，我们检测了人ADPKD肾组织和囊肿衬里上皮细胞系中的PPAR γ表达，发现ADPKD肾组织和囊肿衬里上皮细胞系中的PPAR γ表达高于正常肾组织和人肾皮质（HKC）细胞系。罗格列酮对囊肿衬里上皮细胞的增殖有明显的抑制作用，并呈浓度和时间依赖性。GW 9662是一种特异性的PPAR-gamma拮抗剂，可减弱上述作用。细胞周期分析显示，罗格列酮处理后，人ADPKD囊肿衬里上皮细胞出现G 0/G1期阻滞。细胞周期调控蛋白分析显示，罗格列酮降低增殖细胞核抗原，pRb，细胞周期蛋白D1，细胞周期蛋白D2和Cdk 4的蛋白水平，但增加p21和p27的水平，以剂量依赖性的方式。罗格列酮还可诱导囊肿衬里上皮细胞凋亡，这与bax表达增加和bcl-2表达降低有关。这些结果表明，PPAR-gamma激动剂可能是一种有前途的治疗ADPKD的药物。
Abnormal proliferation is an important pathological feature of autosomal dominant polycystic kidney disease (ADPKD). Many drugs inhibiting cell proliferation have been proved to be effective in slowing the disease progression in ADPKD. Recent evidence has suggested that peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands have anti-neoplasm effects through inhibiting cell growth and inducing cell apoptosis in various cancer cells. In the present study, we examined the expression of PPAR gamma in human ADPKD kidney tissues and cyst-lining epithelial cell line, and found that the expression of PPAR gamma was greater in ADPKD kidney tissues and cyst-lining epithelial cell line than in normal kidney tissues and human kidney cortex (HKC) cell line. Rosiglitazone inhibited significantly proliferation of cyst-lining epithelial cells in a concentration- and time-dependent manner. These effects were diminished by GW9662, a specific PPAR gamma antagonist. Cell cycle analysis showed a G0/G1 arrest in human ADPKD cyst-lining epithelial cells with rosiglitazone treatment. Analysis of cell cycle regulatory proteins revealed that rosiglitazone decreased the protein levels of proliferating cell nuclear antigen, pRb, cyclin D1, cyclin D2 and Cdk4 but increased the levels of p21 and p27 in a dose-dependent manner. Rosiglitazone also induced apoptosis in cyst-lining epithelial cells, which was correlated with increased bax expression and decreased bcl-2 expression. These results suggest PPAR gamma agonist might serve as a promising drug for the treatment of ADPKD.