Apoptosis

, 11:2167

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

  • Yi-Hong Hsin
  • Chi-Hung Cheng
  • Jason T. C. Tzen
  • Ming-Ju Wu
  • Kuo-Hsiung Shu
  • Hong-Chen Chen
Article

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.

Keywords

Aristolochic acid Apoptosis Calcium ER stress GRP78 Kidney 

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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Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Yi-Hong Hsin
    • 1
  • Chi-Hung Cheng
    • 2
  • Jason T. C. Tzen
    • 3
  • Ming-Ju Wu
    • 2
  • Kuo-Hsiung Shu
    • 2
  • Hong-Chen Chen
    • 1
  1. 1.Department of Life Science and the Graduate Institute of Biomedical SciencesNational Chung Hsing UniversityTaichungTaiwan
  2. 2.Section of NephrologyTaichung Veterans General HospitalTaichungTaiwan
  3. 3.Graduate Institute of BiotechnologyNational Chung Hsing UniversityTaichungTaiwan

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