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Abstract
Oxalate, the most common constituent of kidney stones, is an end product of metabolism
that is excreted by the kidney. During excretion, oxalate is transported by a variety
of transport systems and accumulates in renal tubular cells. This process has been
considered benign; however, recent studies on LLC-PK1 cells suggested that high concentrations
of oxalate are toxic, inducing morphological alterations, increases in membrane permeability
to vital dyes and loss of cells from the monolayer cultures. The present studies examined
the basis for oxalate toxicity, focusing on the possibility that oxalate exposure
might increase the production/availability of free radicals in LLC-PK1 cells. Free
radical production was monitored in two ways, by monitoring the reduction of nitroblue
tetrazolium to a blue reaction product and by following the conversion of dihydrorhodamine
123 (DHR) to its fluorescent derivative, rhodamine 123. Such studies demonstrated
that oxalate induces a concentration-dependent increase in dye conversion by a process
that is sensitive to free radical scavengers. Specifically, addition of catalase or
superoxide dismutase blocked the oxalate-induced changes in dye fluorescence/absorbance.
Addition of these free radical scavengers also prevented the oxalate-induced loss
of membrane integrity in LLC-PK1 cells. Thus it seems likely that free radicals are
responsible for oxalate toxicity. The levels of oxalate that induced toxicity in LLC-PK1
cells (350 microM) was only slightly higher than would be expected to occur in the
renal cortex. These considerations suggest that hyperoxaluria may contribute to the
progression of renal injury in several forms of renal disease.