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High ambient glucose levels modulates the production of MMP-9 and alpha 5(IV) collagen by cultured podocytes

机译:高环境葡萄糖水平可调节培养的足细胞产生MMP-9和α5(IV)胶原的能力

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Recent evidences have demonstrated an important role for glomerular visceral epithelial cell ( podocyte) in the development and progression of diabetic nephropathy. We investigated the high-glucose (HG)-triggered signaling pathway and its role in matrix metalloproteinase (MMP) production in murine podocytes. The activity of 92-kDa (MMP-9) gelatinase, but not of 72 kDa (MMP-2), in an HG medium significantly increased during incubation of 2 to 3 days and decreased during incubation of more than 5 days revealed by Gelatin zymography. Opposite to the increases in MMP-9 activity, HG medium produced significant decreases in the protein levels of alpha 5(IV) collagen. Changes in MMP-9 activity were associated with the same pattern as MMP-9 mRNA levels in podocytes exposed to HG media. HG medium rapidly activated ERK1/2 MAPK in podocytes. Moreover, ERK1/2 activation was required for HG-induced enhancement of MMP-9 activity and a decrease in the level of a5( IV) collagen. HG incubation rapidly induced an increase in the nuclear accumulation of Ets-1 protein. Blocking the ERK pathway suppressed HG-induced expression and nuclear accumulation of transcriptional factor Ets-1, and MMP-9 mRNA expression. We suggest that short-or long-term exposure to HG concentrations increases or decreases MMP-9 production and alpha 5(IV) collagen expression in podocytes, this may contribute to the GBM abnormality caused by an imbalance in extracellular matrix (ECM) synthesis and degradation, and may play a critical role in the pathogenesis of proteinuria in diabetic nephropathy. Copyright (c) 2006 S. Karger AG, Basel.
机译:最近的证据表明,肾小球内脏上皮细胞(足细胞)在糖尿病性肾病的发生和发展中起着重要作用。我们调查了高葡萄糖(HG)触发的信号通路及其在鼠足细胞中基质金属蛋白酶(MMP)生产中的作用。明胶酶谱分析显示,在HG培养基中,培养2至3天时,92 kDa(MMP-9)明胶酶的活性显着提高,而在培养5天以上时,其72 kDa(MMP-2)的活性未显着升高。 。与MMP-9活性的增加相反,HG培养基产生的α5(IV)胶原蛋白水平显着下降。 MMP-9活性的变化与暴露于HG培养基的足细胞中MMP-9 mRNA水平的模式相同。 HG培养基可快速激活足细胞中的ERK1 / 2 MAPK。此外,ERK1 / 2激活是HG诱导的MMP-9活性增强和a5(IV)胶原蛋白水平降低所必需的。 HG孵育迅速诱导Ets-1蛋白的核积累增加。阻止ERK通路抑制HG诱导的转录因子Ets-1和MMP-9 mRNA表达以及核积累。我们建议,短期或长期暴露于HG浓度会增加或减少足细胞中MMP-9的产生和α5(IV)胶原的表达,这可能是由于细胞外基质(ECM)合成不平衡和降解,并可能在糖尿病性肾病蛋白尿的发病机理中起关键作用。版权所有(c)2006 S.Karger AG,巴塞尔。

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