Rhein reverses the diabetic phenotype of mesangial cells over-expressing the glucose transporter (GLUT1) by inhibiting the hexosamine pathway
Rhein reverses the diabetic phenotype of mesangial cells over-expressing the glucose transporter (GLUT1) by inhibiting the hexosamine pathway
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DOI：
10.1038/bjp.2008.26
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发表时间：
2008-04-01
影响因子：
7.3
通讯作者：
Liu, Z-H
中科院分区：
文献类型：
--
作者：
Zheng, J-M;Zhu, J-M;Liu, Z-H
背景与目的：大黄酸是从大黄中分离出来的一种蒽醌化合物，已被证明可有效治疗实验性糖尿病肾病（DN）。为了探讨大黄酸对 DN 的治疗作用机制，测试了大黄酸对己糖胺途径的影响。实验方法：评估大黄酸对 MCGT1 细胞中细胞肥大、纤连蛋白合成、葡萄糖摄取、谷氨酰胺：果糖 6-磷酸转氨酶 (GFAT) 活性、UDP-N-乙酰氨基葡萄糖 (UDP-GlcNAc) 水平以及 TGF-β 1 和 p21 表达的影响， GLUT1转基因大鼠系膜细胞系。还测量了高葡萄糖浓度和体外正常大鼠系膜细胞中的 GFAT 活性。 主要结果：在正常葡萄糖浓度培养的 MCGT1 细胞中发现纤连蛋白合成显着增加、细胞肥大、GFAT 活性和 UDP-GlcNAc 水平显着升高以及 TGF-β 1 和 p21 表达增加。大黄酸处理降低了MCGT1细胞的所有这些特征，但并未对GFAT酶活性产生直接影响。结论和意义：MCGT1细胞中己糖胺途径过度活跃，这可能解释了细胞内TGF-β1和p21的较高表达、细胞肥大以及细胞外基质（ECM）成分表达增加。通过抑制己糖胺途径活性的增加，大黄酸降低了 TGF-β1 和 p21 的表达，从而导致细胞肥大和 ECM 合成的减少。抑制己糖胺途径可能是大黄酸在糖尿病肾病中发挥治疗作用的机制之一。
Background and purpose: Rhein, an anthraquinone compound isolated from rhubarb, has been proved effective in treatment of experimental diabetic nephropathy (DN). To explore the mechanism of its therapeutic effect on DN, rhein was tested for its effect on the hexosamine pathway.Experimental approach: The influence of rhein on cellular hypertrophy, fibronectin synthesis, glucose uptake, glutamine: fructose 6-phosphate aminotransferase (GFAT) activity, UDP-N-acetylglucosamine (UDP-GlcNAc) level and TGF-beta 1 and p21 expression was evaluated in MCGT1 cells, a GLUT1 transgenic rat mesangial cell line. GFAT activity in normal rat mesangial cells in high glucose concentrations and in vitro was also measured.Key results: Significantly increased fibronectin synthesis, cellular hypertrophy, much higher GFAT activity and UDP-GIcNAc level and increased TGF-beta 1 and p21 expression were found in MCGT1 cells cultured in normal glucose concentration. Rhein treatment decreased all these features of MCGT1 cells but did not exert a direct effect on GFAT enzymatic activity.Conclusions and implications: There was over-activity of the hexosamine pathway in MCGT1 cells, which may explain the higher expression of TGF-beta 1 and p21, the cellular hypertrophy and the increased expression of extracellular matrix ( ECM) components in the cells. By inhibiting the increased activity the hexosamine pathway, rhein decreased TGF-beta 1 and p21 expression and thus contributed to the decreased cellular hypertrophy and ECM synthesis. Inhibition of the hexosamine pathway may be one of the mechanism through which rhein exerts its therapeutic role in diabetic nephropathy.