N<SUP>G</SUP>-monomethyl-L-arginine inhibits erythropoietin gene expression by stimulating GATA-2

作     者：Tarumoto, T Imagawa, S Ohmine, K Nagai, T Higuchi, M Imai, N Suzuki, N Yamamoto, M Ozawa, K 

作者机构：Univ Tsukuba Inst Clin Med Div Hematol Tsukuba Ibaraki 3058575 Japan Jichi Med Sch Dept Hematol Minami Kawachi Tochigi 32904 Japan Univ Tsukuba Ctr Tsukuba Adv Res Alliance Tsukuba Ibaraki 305 Japan Univ Tsukuba Inst Basic Med Sci Tsukuba Ibaraki 305 Japan Chugai Pharmaceut Co Ltd Tokyo Japan 

出 版 物：《BLOOD》 (血液)

年 卷 期：2000年第96卷第5期

页      面：1716-1722页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

主　　题：缺氧 碱基序列 结合部位/遗传学 环GMP/代谢 DNA/遗传学 DNA/代谢 DNA结合蛋白质类/药物作用 DNA结合蛋白质类/代谢 酶抑制剂/药理学 红细胞生成素/血液 红细胞生成素/遗传学 红细胞生成素/代谢 GATA2转录因子 基因表达调控/药物作用 萤光素酶类/药物作用 萤光素酶类/遗传学 萤光素酶类/代谢 分子序列数据 突变 NG-硝基精氨酸甲酯/药理学 一氧化氮/代谢 启动区(遗传学)/遗传学 蛋白质结合 重组融合蛋白质类/药物作用 重组融合蛋白质类/遗传学 重组融合蛋白质类/代谢 转录因子/药物作用 转录因子/代谢 肿瘤细胞 培养的/细胞学 肿瘤细胞 培养的/药物作用 肿瘤细胞 培养的/代谢 ωN-甲基精氨酸/药理学 动物 人类 小鼠 

摘      要：N-G-monomethyl-L-arginine (L-NMMA) has been reported to be elevated in uremic patients. Based on the hypothesis that the pathogenesis of the anemia of renal disease might be due to the perturbation of transcription factors of the erythropoietin (Epo) gene by L-NMMA, the present study was designed to investigate the effect of L-NMMA on Epo gene expression through the GATA transcription factor. L-NMMA caused decreased levels of Nc, cyclic guanosine monophosphate (cGMP), and Epo protein in Hep3B cells. L-NAME (analogue of L-NMMA) also inhibited Epo production in anemic mice. Transfection of the Epo promoter-luciferase gene into Hep3B cells revealed that L-NMMA inhibited the Epo promoter activity. However, L-NMMA did not inhibit the Epo promoter activity when mutated Epo promoter (GATA to TATA) was transfected, and L-NMMA did not affect the enhancer activity. Electrophoretic mobility shift assays demonstrated the stimulation of GATA binding activity by L-NMMA. However, L-NMMA had no effect on the binding activity of hepatic nuclear factor-4, COUP-TF1, hypoxia-inducing factor-1,or NF-kappa B, Furthermore, cGMP inhibited the L-NMMA-induced GATA binding activity. L-NMMA also increased GATA-2 messenger RNA expression. These results demonstrate that L-NMMA suppresses Epo gene expression by upregulation of the GATA transcription factor and support the hypothesis that L-NMMA is one of the candidate substances that underlie the pathogenesis of renal anemia. (C) 2000 by The American Society of Hematology.