Megalin is downregulated via LPS-TNF-alpha-ERK1/2 signaling pathway in proximal tubule cells
Megalin is downregulated via LPS-TNF-alpha-ERK1/2 signaling pathway in proximal tubule cells
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近曲小管细胞中巨蛋白通过 LPS-TNF-α-ERK1/2 信号通路下调
DOI：
10.1016/j.bbrc.2011.02.118
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发表时间：
2011
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影响因子：
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et al.
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作者：
Takeyama A;et al.
megalin是近端小管细胞（PTC）内吞受体，其表达和功能在糖尿病肾病中降低，参与蛋白尿/白蛋白尿的发生。脂多糖（LPS）在糖尿病血清中通过称为代谢性内毒素血症的机制而慢性增加。我们研究了低水平的LPS介导的信号调节巨蛋白表达的永生化大鼠PTC（IRPTC）。LPS（10 ng/ml）孵育48 h可抑制megalin蛋白的表达及其内吞功能。TNF-α mRNA表达在LPS处理后增加，siRNA敲低TNF-α mRNA可抑制LPS介导的megalin mRNA表达在24 h时的下调。用外源性TNF-α孵育IRPTC也分别在24和48 h时间点抑制megalin mRNA和蛋白表达。MEK 1抑制剂PD 98059部分但显著地竞争TNF-α介导的megalin mRNA表达的下调。总之，低水平LPS介导的TNF-α-ERK 1/2信号通路参与了megalin在IRPTC中表达的下调。
Expression and function of megalin, an endocytic receptor in proximal tubule cells (PTCs), are reduced in diabetic nephropathy, involved in the development of proteinuria/albuminuria. Lipopolysaccharide (LPS) is chronically increased in diabetic sera, by the mechanism called metabolic endotoxemia. We investigated low-level LPS-mediated signaling that regulates megalin expression in immortalized rat PTCs (IRPTCs). Incubation of the cells with LPS (10ng/ml) for 48h suppressed megalin protein expression and its endocytic function. TNF-α mRNA expression was increased by LPS treatment, and knockdown of the mRNA with siRNA inhibited LPS-mediated downregulation of megalin mRNA expression at the 24-h time point. Incubation of IRPTCs with exogenous TNF-α also suppressed megalin mRNA and protein expression at the 24- and 48-h time points, respectively. MEK1 inhibitor PD98059 competed partially but significantly TNF-α-mediated downregulation of megalin mRNA expression. Collectively, low-level LPS-mediated TNF-α-ERK1/2 signaling pathway is involved in downregulation of megalin expression in IRPTCs.