Wu Liyu, Derynck Rik
Department of Cell and Tissue Biology, Programs in Cell Biology and Developmental Biology, University of California, San Francisco, CA 94143, USA.
Dev Cell. 2009 Jul;17(1):35-48. doi: 10.1016/j.devcel.2009.05.010.
In multicellular organisms, cell size is tightly controlled by nutrients and growth factors. Increasing ambient glucose induces enhanced protein synthesis and cell size. Continued exposure of cells to high glucose in vivo, as apparent under pathological conditions, results in cell hypertrophy and tissue damage. We demonstrate that activation of TGF-beta signaling has a central role in glucose-induced cell hypertrophy in fibroblasts and epithelial cells. Blocking the kinase activity of the TbetaRI receptor or loss of its expression prevented the effects of high glucose on protein synthesis and cell size. Exposure of cells to high glucose induced a rapid increase in cell surface levels of the TbetaRI and TbetaRII receptors and a rapid activation of TGF-beta ligand by matrix metalloproteinases, including MMP-2 and MMP-9. The consequent autocrine TGF-beta signaling in response to glucose led to Akt-TOR pathway activation. Accordingly, preventing MMP-2/MMP-9 or TGF-beta-induced TOR activation inhibited high glucose-induced cell hypertrophy.
在多细胞生物体中，细胞大小受到营养物质和生长因子的严格控制。环境葡萄糖浓度升高会诱导蛋白质合成增加和细胞体积增大。在体内，细胞持续暴露于高葡萄糖环境下（如在病理条件下所见），会导致细胞肥大和组织损伤。我们证明，转化生长因子-β（TGF-β）信号通路的激活在成纤维细胞和上皮细胞的葡萄糖诱导的细胞肥大中起核心作用。阻断TβRI受体的激酶活性或其表达缺失可防止高葡萄糖对蛋白质合成和细胞大小的影响。细胞暴露于高葡萄糖会导致TβRI和TβRII受体的细胞表面水平迅速增加，以及基质金属蛋白酶（包括MMP-2和MMP-9）对TGF-β配体的快速激活。由此产生的对葡萄糖的自分泌TGF-β信号通路导致Akt-TOR信号通路激活。因此，抑制MMP-2/MMP-9或TGF-β诱导的TOR激活可抑制高葡萄糖诱导的细胞肥大。
