NMDA Agonists and Antagonists Induce Renal Culture Cell Toxicity

The NMDA receptor (NMDAR) is expressed in the renal proximal tubule. NMDAR agonists and antagonists induce cell toxicity in the central nervous system (CNS). We studied the effect of NMDAR agonists and antagonists on renal cell survival in renal culture cells: proximal tubule-like opossum kidney (OK) and distal-tubule-like madine darby canine kidney cells (MDCK) cells. Low dose glutamate had no effect on cell survival. However, 10 mM glutamate induced a 14-fold increase in cell death compared to control cells. Addition of low or high doses of the NMDAR agonist glycine had no effect on cell toxicity. Exposure of cells to the non-competitive NMDAR blocker MK-801 or the competitive NMDAR antagonist CPP induced a time and dose-dependent increase in cell death and apoptosis. The presence of fetal bovine serum in the pre-incubation media attenuated the toxicity caused by MK-801 and CPP. The deleterious effect of NMDAR antagonists on cell survival was specific for OK cells; these substances had no effect on MDCK cell survival. Finally, pre-treatment of OK cells with the renal cytoprotective glycine completely blunted the affect of MK-801 on renal cell survival. We conclude that excessive stimulation or blockade of the renal NMDAR results in cell death.