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.