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
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
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DOI：
10.1172/jci117004
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发表时间：
1994-02-01
影响因子：
15.9
通讯作者：
WOLF, G
中科院分区：
文献类型：
--
作者：
ZIYADEH, FN;SHARMA, K;WOLF, G
以往的研究表明，高糖培养的肾小球系膜细胞可以刺激细胞外基质的合成，也可以增加转化生长因子-β的表达。我们测试了对细胞外基质产生的刺激是否由转化生长因子-β的自分泌激活所介导，转化生长因子-β是一种已知的促硬化细胞因子。加入中和的抗转化生长因子-β抗体，而不是正常的兔免疫球蛋白，显著降低高糖刺激的(3)[H]Pro的掺入。变性SDS-PAGE显示，高浓度(450 mg/dl)D-葡萄糖刺激的主要是I型和IV型胶原。这种高糖介导的胶原合成增加可被抗转化生长因子-β抗体抑制。用2 ng/ml重组转化生长因子-β(1)处理正常(100 mg/dl)D-葡萄糖培养的肾小球系膜细胞，与高糖的作用相似。此外，抗转化生长因子-β抗体显著降低高糖诱导的α2(I)和α1(IV)胶原基因表达水平的升高。因此，高糖刺激的系膜细胞胶原生成的增加至少部分是由自分泌的转化生长因子-β激活所介导的。我们推测，阻断肾小球转化生长因子-β的活性可能是治疗糖尿病肾病的一种有效干预措施。
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.