Effect of aristolochic acid on intracellular calcium concentration and its links with apoptosis in renal tubular cells |
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Authors: | Yi-Hong Hsin Chi-Hung Cheng Jason T C Tzen Ming-Ju Wu Kuo-Hsiung Shu Hong-Chen Chen |
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Institution: | (1) Department of Life Science and the Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan;(2) Section of Nephrology, Taichung Veterans General Hospital, Taichung, 40705, Taiwan;(3) Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, 40227, Taiwan |
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Abstract: | Aristolochic acid (AA) has been demonstrated to play a causal role in Chinese herbs nephropathy. However, the detailed mechanism
for AA to induce apoptosis of renal tubular cells remains obscure. In this study, we show that AA evokes a rapid rise in the
intracellular Ca2+ concentration of renal tubular cells through release of intracellular endoplasmic reticulum Ca2+ stores and influx of extracellular Ca2+, which in turn causes endoplasmic reticulum stress and mitochondria stress, resulting in activation of caspases and finally
apoptosis. Ca2+ antagonists, including calbindin-D28k (an intracellular Ca2+ buffering protein) and BAPTA-AM (a cell-permeable Ca2+ chelator), are capable of ameliorating endoplasmic reticulum stress and mitochondria stress, and thereby enhance the resistance
of the cells to AA. Moreover, we show that overexpression of the anti-apoptotic protein Bcl-2 in combination with BAPTA-AM
treatment can provide renal tubular cells with almost full protection against AA-induced cytotoxicity. In conclusion, our
results demonstrate an impact of AA to intracellular Ca2+ concentration and its link with AA-induced cytotoxicity.
Yi-Hong Hsin and Chi-Hung Cheng are equally contributed to this work. |
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Keywords: | Aristolochic acid Apoptosis Calcium ER stress GRP78 Kidney |
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