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首页> 外文期刊>American Journal of Physiology >Hexosamines and TGF-beta1 use similar signaling pathways to mediate matrix protein synthesis in mesangial cells.
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Hexosamines and TGF-beta1 use similar signaling pathways to mediate matrix protein synthesis in mesangial cells.

机译：六胺和TGF-β1使用类似的信号通路来介导肾小球膜细胞中的基质蛋白合成。

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摘要

Hyperglycemia-induced alterations in mesangial (MES) cell function and extracellular matrix (ECM) protein accumulation are seen in diabetic glomerulopathy. Transforming growth factor-beta1 (TGF-beta1) mediates high-glucose-induced matrix production in the kidney. Recent studies demonstrated that some of the effects of high glucose on cellular metabolism are mediated by the hexosamine biosynthesis pathway (HBP) in which fructose-6-phosphate is converted to glucosamine (GlcN) 6-phosphate. We previously showed that the high-glucose-mediated fibronectin and laminin synthesis in MES cells is mediated by the HBP and that GlcN is more potent than glucose in inducing TGF-beta1 promoter luciferase activity. In this study, we investigated the hypothesis that the effects of glucose on MES matrix production occur via hexosamine regulation of TGF-beta1. Culturing simian virus (SV)-40-transformed rat kidney MES cells in 25 mM glucose (HG) for 48 h increases cellular fibronectin and laminin levels about twofold on Western blots compared with low glucose (5 mM). GlcN (1.5 mM) or TGF-beta1 (2.5-5 ng/ml) for 24-48 h also increases ECM synthesis. However, the effects of HG or GlcN with TGF-beta1 are not additive. The presence of anti-TGF-beta1 antibodies (20 microg/ml) blocks both TGF-beta1- and GlcN-induced fibronectin synthesis. TGF-beta1 increased ECM levels via PKA (laminin and fibronectin) and PKC (fibronectin) pathways. Similarly, TGF-beta1 and hexosamines led to nonadditive increases in phosphorylation of the cAMP responsive element binding transcription factor. These results suggest that the effects of excess glucose on MES ECM synthesis occur via HBP-mediated regulation of TGF-beta1.
机译：在糖尿病性肾小球病中可以看到高血糖诱导的肾小球系膜（MES）细胞功能和细胞外基质（ECM）蛋白积累的改变。转化生长因子-beta1（TGF-beta1）介导高葡萄糖诱导的肾脏基质生成。最近的研究表明，高葡萄糖对细胞代谢的某些影响是由己糖胺生物合成途径（HBP）介导的，在该途径中，果糖6-磷酸被转化为氨基葡萄糖（GlcN）6-磷酸。我们以前表明，MES细胞中高葡萄糖介导的纤连蛋白和层粘连蛋白合成是由HBP介导的，并且GlcN在诱导TGF-β1启动子荧光素酶活性方面比葡萄糖更有效。在这项研究中，我们调查了葡萄糖对MES基质产生的影响是通过TGF-beta1的六胺调节产生的。在25 mM葡萄糖（HG）中培养猿猴病毒（SV）-40转化的大鼠肾脏MES细胞48小时，与低葡萄糖（5 mM）相比，Western印迹显示细胞纤连蛋白和层粘连蛋白水平提高约两倍。 GlcN（1.5 mM）或TGF-beta1（2.5-5 ng / ml）持续24-48小时也能增加ECM合成。但是，HG或GlcN与TGF-beta1的作用不是累加的。抗TGF-β1抗体（20微克/毫升）的存在会阻断TGF-β1和GlcN诱导的纤连蛋白合成。 TGF-beta1通过PKA（纤溶酶和纤连蛋白）和PKC（纤连蛋白）途径增加了ECM水平。同样，TGF-beta1和己糖胺导致cAMP响应元件结合转录因子磷酸化的非累加性增加。这些结果表明过量的葡萄糖对MES ECM合成的影响是通过HBP介导的TGF-beta1调节而发生的。

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