Variable sensitivity to diethylene glycol poisoning is related to differences in the uptake transporter for the toxic metabolite diglycolic acid

Abstract

Introduction/Context

Poisonings with diethylene glycol are characterized by acute kidney injury and peripheral neuropathy. In animal studies on the toxicities of diethylene glycol and its metabolite diglycolic acid, remarkable differences in susceptibility to acute kidney injury were observed in identically-dosed rats. In those studies, only about 60% showed acute kidney injury, yet all rats with acute kidney injury showed marked diglycolic acid accumulation in tissues, while no diglycolic acid accumulated in rats without injury. Diglycolic acid is taken into renal cells via sodium-dependent dicarboxylate transporters. When sodium-dependent dicarboxylate transporter-1 is inhibited or knocked down in human kidney cells, diglycolic acid uptake and toxicity are reduced. We hypothesize that the variation in sensitivity to tissue diglycolic acid retention and to diethylene glycol/diglycolic acid toxicity is explained by differential expression of sodium-dependent dicarboxylate transporter-1 in rat kidneys.

Methods

Using kidney tissue from previous studies, we performed rt-PCR analysis of sodium-dependent dicarboxylate transporter-1 mRNA. In those studies, Wistar-Han rats were either gavage with diethylene glycol 6 g/kg every 12 h for 7 days or with single doses of diglycolic acid 300 mg/kg. Kidney tissue was harvested after euthanasia and preserved in formalin. Tissue slices were homogenized and RNA was isolated using an RNAstorm FFPE RNA Isolation Kit. The expression of sodium-dependent dicarboxylate transporter-1 mRNA was compared between groups that showed diglycolic acid accumulation and acute renal injury with those that showed no diglycolic acid accumulation or toxicity.

Results

Significantly higher expression of sodium-dependent dicarboxylate transporter-1 mRNA was present in the kidneys of rats with acute kidney injury and diglycolic acid accumulation compared to those in rats that had no diglycolic acid in their kidneys and no acute kidney injury.

Discussion

The likelihood of acute kidney injury after dosing of rats with diethylene glycol or diglycolic acid is linked with an enhanced ability to take up diglycolic acid into renal cells via the sodium-dependent dicarboxylate transporter-1. The variability in diethylene glycol toxicity in humans, as reported in epidemiological studies, may also be linked with differences in tissue uptake of diglycolic acid.

Conclusions

Animals with acute kidney injury after exposure to diethylene glycol or diglycolic acid had higher sodium-dependent dicarboxylate transporter-1 expression and greater diglycolic acid accumulation in renal tissues than animals without acute kidney injury.

Keywords:

• Diethylene glycol
• diglycolic acid
• dicarboxylate transporters
• renal uptake
• genetic expression
• rat model

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by the NIH, grant [R15 ES029704], and by a research agreement with the Ethylene Glycol Panel of the American Chemistry Council.