Effect of aristolochic acid on intracellular calcium concentration and its links with apoptosis in renal tubular cells.
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 Ca(2+) concentration of renal tubular cells through release of intracellular endoplasmic reticulum Ca(2+) stores and influx of extracellular Ca(2+), which in turn causes endoplasmic reticulum stress and mitochondria stress, resulting in activation of caspases and finally apoptosis. Ca(2+) antagonists, including calbindin-D(28k) (an intracellular Ca(2+) buffering protein) and BAPTA-AM (a cell-permeable Ca(2+) 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 Ca(2+) concentration and its link with AA-induced cytotoxicity.
Hsin
Yi-Hong
YH
Department of Life Science and the Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.
Cheng
Chi-Hung
CH
Tzen
Jason T C
JT
Wu
Ming-Ju
MJ
Shu
Kuo-Hsiung
KH
Chen
Hong-Chen
HC
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D034341:Aristolochic Acids / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D004285:Dogs; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013552:Swine
D000998:Antiviral Agents; D034341:Aristolochic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D004533:Egtazic Acid; C000228:aristolochic acid I; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium