ZFIN ID: ZDB-PUB-150703-7
Impairment of the cellular distribution and stability of the erythropoietin receptor through the direct targeting of aristolochic acid
Chen, Y.H., Chou, C.Y., Sun, C.Y.
Date: 2015
Source: Toxicological sciences : an official journal of the Society of Toxicology   147(1): 246-54 (Journal)
Registered Authors: Chen, Yau-Hung
Keywords: Anemia, Aristolochic acid, Erythropoietin receptor, Lysosome, Molecular docking
MeSH Terms:
  • Anemia/chemically induced
  • Anemia/metabolism
  • Anemia/pathology
  • Animals
  • Aristolochic Acids/toxicity*
  • Cell Line
  • Cell Membrane/drug effects
  • Cell Membrane/metabolism
  • Humans
  • Kidney Diseases/chemically induced
  • Kidney Diseases/metabolism
  • Kidney Diseases/pathology
  • Lysosomes/drug effects
  • Molecular Docking Simulation
  • Receptors, Erythropoietin/drug effects*
  • Signal Transduction/drug effects
  • Zebrafish
PubMed: 26136230 Full text @ Toxicol. Sci.
ABSTRACT
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 co-localizes 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, co-treatment 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.
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