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高糖通过自分泌激活转化生长因子-β介导小鼠系膜细胞中胶原基因表达和蛋白质合成的刺激。

Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-beta.

作者信息

Ziyadeh F N, Sharma K, Ericksen M, Wolf G

机构信息

Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6144.

出版信息

J Clin Invest. 1994 Feb;93(2):536-42. doi: 10.1172/JCI117004.

DOI:10.1172/JCI117004
PMID:8113392
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC293875/
Abstract

Previous investigations have demonstrated that growing mesangial cells in high glucose concentration stimulates extracellular matrix synthesis and also increases the expression of TGF-beta. We tested whether the stimulation of extracellular matrix production is mediated by autocrine activation of TGF-beta, a known prosclerotic cytokine. Addition of neutralizing anti-TGF-beta antibody, but not normal rabbit IgG, significantly reduced the high glucose-stimulated incorporation of 3[H]proline. Denaturing SDS-PAGE revealed that mainly collagen types I and IV were stimulated by high (450 mg/dl) D-glucose. This high glucose-mediated increase in collagen synthesis was reduced by the anti-TGF-beta antibody. Treatment of mesangial cells grown in normal (100 mg/dl) D-glucose with 2 ng/ml recombinant TGF-beta 1 mimicked the effects of high glucose. Furthermore, the anti-TGF-beta antibody significantly reduced the increase in mRNA levels encoding alpha 2(I) and alpha 1(IV) collagens induced by high glucose. Thus, the high glucose-stimulated increase of collagen production in mesangial cells is mediated, at least in part, by autocrine TGF-beta activation. We postulate that the interception of the glomerular activity of TGF-beta may be an effective intervention in the management of diabetic nephropathy.

摘要

先前的研究表明，在高葡萄糖浓度下培养系膜细胞会刺激细胞外基质合成，并且还会增加转化生长因子-β（TGF-β）的表达。我们测试了细胞外基质产生的刺激是否由TGF-β（一种已知的促硬化细胞因子）的自分泌激活介导。添加中和性抗TGF-β抗体，而非正常兔IgG，可显著降低高葡萄糖刺激的3[H]脯氨酸掺入。变性SDS-PAGE显示，高（450mg/dl）D-葡萄糖主要刺激I型和IV型胶原。抗TGF-β抗体可降低这种高葡萄糖介导的胶原合成增加。用2ng/ml重组TGF-β1处理在正常（100mg/dl）D-葡萄糖中生长的系膜细胞，可模拟高葡萄糖的作用。此外，抗TGF-β抗体可显著降低高葡萄糖诱导的编码α2（I）和α1（IV）胶原的mRNA水平增加。因此，高葡萄糖刺激的系膜细胞胶原产生增加至少部分是由自分泌TGF-β激活介导的。我们推测，阻断TGF-β的肾小球活性可能是糖尿病肾病管理中的一种有效干预措施。

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