High glucose-induced transforming growth factor β1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells
High glucose-induced transforming growth factor β1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells
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DOI：
10.1172/jci119875
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发表时间：
1998-01-01
影响因子：
15.9
通讯作者：
Schleicher, ED
中科院分区：
文献类型：
--
作者：
Kolm-Litty, V;Sauer, U;Schleicher, ED
先前的研究表明，肾小球系膜细胞暴露于高浓度葡萄糖诱导TGF-β 1介导的基质蛋白的产生，我们测试了D-葡萄糖的结构类似物是否可以模拟高糖效应，发现D-氨基葡萄糖在增强TGF-β 1的产生方面比D-葡萄糖本身更有效。β蛋白以及随后基质组分硫酸乙酰肝素蛋白聚糖和纤连蛋白的产生呈时间和剂量依赖性，D-氨基葡萄糖还促进潜伏TGF-β转化为活性形式，因此，我们认为氨基己糖生物合成途径（其关键酶是谷氨酰胺：果糖-6-磷酸酰胺转移酶[GFAT]）有助于高糖诱导的TGF-β 1产生。通过底物类似物阿扎胞苷或通过用反义寡核苷酸抑制GFAT蛋白合成来抑制GFAT防止了高糖诱导的细胞葡糖胺代谢物和TGF-β 1表达和生物活性的增加以及随后对系膜细胞增殖和基质产生的影响。总体而言，我们的研究表明，通过GFAT催化的己糖胺生物合成途径的葡萄糖代谢通量参与葡萄糖诱导的系膜TGF-β的产生。β导致基质产量增加。
Previous studies revealed that exposure of mesangial cells to high glucose concentration induces the production of matrix proteins mediated by TGF-beta 1, We tested if structural analogues of D-glucose may mimic the high glucose effect and found that D-glucosamine was strikingly more potent than D-glucose itself in enhancing the production of TGF-beta protein and subsequent production of the matrix components heparan sulfate proteoglycan and fibronectin in a time-and dose-dependent manner, D-Glucosamine also promoted conversion of latent TGF-beta to the active form, Therefore, we suggested that the hexosamine biosynthetic pathway (the key enzyme of which is glutamine:fructose-6-phosphate amidotransferase [GFAT]) contributes to the high glucose-induced TGF-beta 1 production. Inhibition of GFAT by the substrate analogue azaserine or by inhibition of GFAT protein synthesis with antisense oligonucleotide prevented the high glucose-induced increase in cellular glucosamine metabolites and TGF-beta 1 expression and bioactivity and subsequent effects on mesangial cell proliferation and matrix production, Overall, our study indicates that the flux of glucose metabolism through the GFAT catalyzed hexosamine biosynthetic pathway is involved in the glucose-induced mesangial production of TGF-beta leading to increased matrix production.