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Effect of aristolochic acid on intracellular calcium concentration and its links with apoptosis in renal tubular cells

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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.

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Abbreviations

ER:

endoplasmic reticulum

GRP:

glucose-regulated protein

AA:

aristolochic acid

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

BAPTA-AM:

1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid

ZVAD-fmk:

benzyloxycarbonyl-Phe-Val-Ala-Asp (Ome)-fluoromethyl-ketone

MDCK:

Madin-Darby canine kidney

COX4:

cytochrome oxidase subunit IV

PBS:

phosphate-buffered saline

[Ca2+]i :

intracellular calcium concentration

PLA2 :

phospholipase A2

CsA:

cyclosporine A

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Authors and Affiliations

  1. Department of Life Science and the Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan

    Yi-Hong Hsin & Hong-Chen Chen

  2. Section of Nephrology, Taichung Veterans General Hospital, Taichung, 40705, Taiwan

    Chi-Hung Cheng, Ming-Ju Wu & Kuo-Hsiung Shu

  3. Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, 40227, Taiwan

    Jason T. C. Tzen

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  1. Yi-Hong Hsin
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  2. Chi-Hung Cheng
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  5. Kuo-Hsiung Shu
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Correspondence to Hong-Chen Chen.

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Yi-Hong Hsin and Chi-Hung Cheng are equally contributed to this work.

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Hsin, YH., Cheng, CH., Tzen, J.T.C. et al. Effect of aristolochic acid on intracellular calcium concentration and its links with apoptosis in renal tubular cells. Apoptosis 11, 2167–2177 (2006). https://doi.org/10.1007/s10495-006-0289-0

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