Oxalate toxicity in renal epithelial cells: Characteristics of apoptosis and necrosis

Studies in various tissues, including the kidney, have demonstrated that to xins elicit apoptosis under certain conditions and necrosis under others. T he nature of the response has important consequences for the injured tissue in that necrotic cells elicit inflammatory responses, whereas apoptotic ce lls do not. Thus, there has been considerable interest in defining the mode of cell death elicited by known cytotoxins. The present studies examined t he response of renal epithelial cells to oxalate, a metabolite excreted by the kidney that produces oxidant stress and death of renal cells at pathoph ysiological concentrations. These studies employed LLC-PK1 cells, a renal e pithelial cell line from pig kidney and NRK-52E (NRK) cells, a line from no rmal rat kidney, and compared the effects of oxalate with those of known ap optotic agents. Changes in cellular and nuclear morphology, in nuclear size , in ceramide production, and in DNA integrity were assessed. The ability o f bcl-2, an anti-apoptotic gene product, to attenuate oxalate toxicity was also assessed. These studies indicated that oxalate-induced death of renal epithelial cells exhibits several features characteristic of apoptotic cell death, including increased production of ceramide, increased abundance of apoptotic bodies, and marked sensitivity to the level of expression of the anti-apoptotic gene bcl-2. Oxalate-induced cell death also exhibits several characteristics of necrotic cell death in that the majority of the cells e xhibited cellular and nuclear swelling after oxalate treatment and showed l ittle evidence of DNA cleavage by TUNEL assay. These results suggest that t oxic concentrations of oxalate trigger both forms of cell death in renal ep ithelial cells. (C) 2000 Academic Press.