Chiang Wen-Chih, Teng Che-Ming, Lin Shuei-Liong, Chen Yung-Ming, Tsai Tun-Jun, Hsieh Bor-Shen
Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10016, Taiwan.
Eur J Pharmacol. 2005 Jul 4;517(1-2):1-10. doi: 10.1016/j.ejphar.2005.04.046.
This study was designed to investigate the effect of 1-benzyl-3-(5'-hydroxymethyl-2'-furyl) indazole (YC-1), a guanylate cyclase activator, upon the proliferation of rat mesangial cells and its underlying mechanism. YC-1 inhibited cell proliferation and DNA synthesis in a dose- and time-dependent manner. Flow cytometry cell-cycle studies revealed that YC-1 prevented the entry of cells from G1 into S phase. The expression of cyclin D1 and the kinase activity of cyclin D1/cyclin-dependent kinase (CDK)4 were lower within YC-1-treated cells, revealed by Western blotting, Northern blotting and kinase assays. YC-1 did not increase the intracellular cGMP concentration in mesangial cells. Inhibitors of soluble guanylate cyclase, protein kinase G, or protein kinase A also did not reverse the inhibitory effect elicited by YC-1, while co-treatment with p38 mitogen-activated protein kinase (MAPK) inhibitor could partially reverse the suppressive effect. YC-1 inhibited proliferation of mesangial cells and induced cell-cycle arrest by the reduction of cyclin D1 synthesis and cyclin D1/CDK4 kinase activity. This effect acts partially through p38 MAPK signal transduction activation and is independent of cGMP-signaling pathways.
本研究旨在探讨鸟苷酸环化酶激活剂1-苄基-3-(5'-羟甲基-2'-呋喃基)吲唑(YC-1)对大鼠系膜细胞增殖的影响及其潜在机制。YC-1以剂量和时间依赖性方式抑制细胞增殖和DNA合成。流式细胞术细胞周期研究显示，YC-1可阻止细胞从G1期进入S期。蛋白质印迹法、Northern印迹法和激酶分析显示，在经YC-1处理的细胞中，细胞周期蛋白D1的表达及细胞周期蛋白D1/细胞周期蛋白依赖性激酶(CDK)4的激酶活性较低。YC-1并未增加系膜细胞内的cGMP浓度。可溶性鸟苷酸环化酶、蛋白激酶G或蛋白激酶A的抑制剂也不能逆转YC-1所引发的抑制作用，而与p38丝裂原活化蛋白激酶(MAPK)抑制剂联合处理可部分逆转这种抑制作用。YC-1通过减少细胞周期蛋白D1的合成及细胞周期蛋白D1/CDK4激酶活性来抑制系膜细胞增殖并诱导细胞周期停滞。这种作用部分通过p38 MAPK信号转导激活发挥，且独立于cGMP信号通路。
