Cisplatin, gentamicin, and p-aminophenol induce markers of endoplasmic reticulum stress in the rat kidneys.

In vitro evidence of the involvement of the endoplasmic reticulum (ER) during drug-induced renal toxicity is accumulating. ER stress and ER-mediated cell death markers have been reported after exposure of renal cells to model toxicants and nephrotoxic drugs in various in vitro models, but in vivo experiments with clinically relevant nephrotoxic compounds are lacking. In order to determine the relevance of the in vitro findings, markers of ER stress (XBP1 messenger RNA processing and protein expression; GRP78 and GRP94 upregulation) and ER-mediated cell death (caspase-12 and calpain activation) were examined in kidney tissue of rats exposed to nephrotoxic doses of cisplatin (CIS), gentamicin (GEN), and p-aminophenol (PAP), a nephrotoxic metabolite of acetaminophen. XBP1 signaling was observed with all three drugs and was associated with increased expression of GRP94 and GRP78 in GEN- and PAP-treated animals, but surprisingly not after CIS exposure. m-Calpain expression was increased after 7 days of CIS treatment, whereas it was decreased in PAP-treated rats. Caspase-12 cleavage products were increased after CIS, GEN, and PAP administration. The results of this study demonstrate that three clinically relevant nephrotoxic drugs are all associated with changes in markers of ER stress and ER-mediated cell death in vivo. Further investigation is warranted to determine the role of the ER, the calpain system, and caspase-12 in drug-induced renal cell death.