Cisplatin, Gentamicin, and p-Aminophenol Induce Markers of Endoplasmic Reticulum Stress in the Rat Kidneys

Abstract

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.

Endoplasmic reticulum stress as a novel target to ameliorate epithelial-to-mesenchymal transition and apoptosis of human peritoneal mesothelial cells

“…26,52 Cytoprotection by ER stress preconditioning was also confirmed in cultured renal tubular cells exposed to nephrotoxic drugs via the induction of GRP78 and an enhancement of ER folding capacity. [53][54][55] In this study, preconditioning targeting ER stress ameliorated TGF-β1-induced EMT and apoptosis in HPMCs, suggesting the role of ER as a potential target for protecting the peritoneal membrane. ER stress preconditioning in HPMCs may enhance the maturation of protein by enhancing GRP expression, which resulted in the preservation of peritoneal membrane integrity.…”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…Indeed, markers of ER stress such as increased BiP/GRP78 and CHOP expression and caspase 12 activation have been found in different investigations performed in renal cells and kidneys of rodents treated with cisplatin (Liu and Baliga 2005; Peyrou et al. 2007; Khan et al. 2013; Kong et al.…”

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

“…8,9 ER stress is associated with a range of diseases, including ischemia/reperfusion injury, neuronal degeneration, and diabetes. 3,5,10 -12 Accumulating evidence, including our previous studies, suggests a pathophysiologic role of ER stress in the kidney, [13][14][15][16][17][18][19] the details of which remain unclear. Here, we investigated whether therapeutic approaches targeting ER stress might be effective against renal disease using a model of mesangioproliferative glomerulonephritis in rats.…”