Renal toxicity of ethylene glycol results from internalization of calcium oxalate crystals by proximal tubule cells

Ethylene glycol exposure can lead to the development of renal failure due to the metabolic formation of calcium oxalate monohydrate (COM) crystals. The renal damage is closely linked to the degree of COM accumulation in the kidney and most likely results from a COM-induced injury to proximal tubule (PT) cells. The present studies have measured the binding and internalization of COM by primary cultures of normal PT cells from humans and from Wistar and Fischer-344 rats in order to examine the roles of these uptake processes in the resulting cytotoxicity. Internalization was determined by incubation of cells with [14C]-COM at 37 °C, removal of bound COM with an EDTA incubation, followed by solubilization of cells, as well as by transmission electron microscopy of COM-exposed cells. COM crystals were internalized by PT cells in time- and concentration-dependent manners. COM crystals were bound to and internalized by rat cells about five times more than by human cells. Binding and internalization values were similar between PT cells from Wistar and Fischer-344 rats, indicating that a differential uptake of COM does not explain the known strain difference in sensitivity to ethylene glycol renal toxicity. Internalization of COM correlated highly with the degree of cell death, which is greater in rat cells than in human cells. Thus, surface binding and internalization of COM by cells play critical roles in cytotoxicity and explain why rat cells are more sensitive to COM crystals. At the same level of COM accumulation after ethylene glycol exposure or hyperoxaluria in vivo, rats would be more susceptible than humans to COM-induced damage.