Impairment of the Cellular Distribution and Stability of the Erythropoietin Receptor Through the Direct Targeting of Aristolochic Acid.

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 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.

• Authors: Yau-Hung Chen, Chi-Yuan Chou, Chiao-Yin Sun
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 147 Issue 1 Pg. 246-54 (Sep 2015) ISSN: 1096-0929 [Electronic] United States
• PMID: 26136230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Aristolochic Acids
• Receptors, Erythropoietin
• aristolochic acid I

Topics

• Anemia (chemically induced, metabolism, pathology)
• Animals
• Aristolochic Acids (toxicity)
• Cell Line
• Cell Membrane (drug effects, metabolism)
• Humans
• Kidney Diseases (chemically induced, metabolism, pathology)
• Lysosomes (drug effects)
• Molecular Docking Simulation
• Receptors, Erythropoietin (drug effects)
• Signal Transduction (drug effects)
• Zebrafish