淡江大學機構典藏:Item 987654321/109598
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    题名: Impairment of the Cellular Distribution and Stability of the Erythropoietin Receptor Through the Direct Targeting of Aristolochic Acid
    作者: Chen YH;Chou CY;Sun CY
    关键词: anemia;aristolochic acid;erythropoietin receptor;lysosome;molecular docking
    日期: 2015-06-30
    上传时间: 2017-02-24 02:12:23 (UTC+8)
    出版者: Oxford University Press
    摘要: Aristolochic acid (AA) nephropathy is complicated with early onset and severe anemia. The molecular pathological mechanism of AA-induced anemia remains unclear. The aim of this study was to evaluate the putative pathological roles of the erythropoietin receptor (EPOR) in AA-induced anemia in both AA nephropathy zebrafish and cultured human renal tubular cells (HK2). Immunofluorescence staining experiments revealed that AA colocalizes with the EPOR in zebrafish embryos as well as in the cytoplasm of HK2 cells. After exogenous EPO stimulation, the EPOR was detected in the plasma membrane of HK cells. However, cotreatment with AA and EPO inhibited EPOR signaling and its membrane localization upon EPO stimulation. The results of studies with a protein synthesis inhibitor and a lysosome inhibitor revealed that AA accelerates the lysosomal degradation of EPOR. The molecular docking results suggest that AA may interact with the N-terminus of EPOR. Together with the results of light absorption and in vitro competition assays, we concluded that AA treatment impairs EPOR membrane localization, accelerates its lysosomal degradation, and consequently downregulates EPOR signaling by direct targeting. The results of this study may further detail the pathological mechanism of severe anemia complicated with AA nephropathy.
    關聯: Toxicological Sciences 147(1), p.246-254
    DOI: 10.1093/toxsci/kfv125
    显示于类别:[化學學系暨研究所] 期刊論文

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