BACKGROUND: Oxalate, a common constituent of kidney stones, is cytotoxic for renal epithelial cells. Although the exact mechanism of oxalate-induced cell death remains unclear, studies in various cell types, including renal epithelial cells, have implicated phospholipase A2 (PLA2) as a prominent mediator of cellular injury. Thus, these studies examined the role of PLA2 in the cytotoxic effects of oxalate. METHODS: The release of [3H]-arachidonic acid (AA) or [3H]-oleic acid (OA) from prelabeled Madin-Darby canine kidney (MDCK) cells was measured as an index for PLA2 activity. The cell viability was assessed by the exclusion of ethidium homodimer-1. RESULTS: Oxalate exposure (175 to 550 microM free) increased the release of [3H]-AA in MDCK cells but had no effect on the release of [3H]-OA. Oxalate-induced [3H]-AA release was abolished by arachidonyl trifluoromethyl ketone (AACOCF3), a selective inhibitor of cytosolic PLA2 (cPLA2), but was not affected by selective inhibitors of secretory PLA2 and calcium-independent PLA2. The [3H]-AA release could be demonstrated within 15 minutes after exposure to oxalate, which is considerably earlier than the observed changes in cell viability. Furthermore, AACOCF3 significantly reduced oxalate toxicity in MDCK cells. CONCLUSIONS: Oxalate increases AA release from MDCK cells by a process involving cPLA2. In addition, based on the evidence obtained using a selective inhibitor of this isoform, it would appear that the activity of this enzyme is responsible, at least in part, for the cytotoxic effects of oxalate. The finding that oxalate can trigger a known lipid-signaling pathway may provide new insight into the initial events in the pathogenesis of nephrolithiasis.