Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, LA, USA.
Clin Toxicol (Phila). 2023 Apr;61(4):207-211. doi: 10.1080/15563650.2022.2163659. Epub 2023 Mar 20.
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 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.
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.
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.
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 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.
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.
简介/背景：乙二醇中毒的特征是急性肾损伤和周围神经病变。在乙二醇及其代谢产物二甘醇毒性的动物研究中，同样剂量的大鼠对急性肾损伤的易感性存在显著差异。在这些研究中，只有约 60%的大鼠出现急性肾损伤，但所有出现急性肾损伤的大鼠组织中均有明显的二甘酸积聚，而无损伤的大鼠则没有二甘酸积聚。二甘酸通过钠依赖性二羧酸转运体进入肾细胞。当人肾细胞中的钠依赖性二羧酸转运体-1 被抑制或敲除时，二甘酸的摄取和毒性会降低。我们假设，组织中二甘酸保留和乙二醇/二甘酸毒性敏感性的差异是由大鼠肾脏中钠依赖性二羧酸转运体-1 的差异表达解释的。
使用先前研究中的肾组织，我们进行了钠依赖性二羧酸转运体-1 mRNA 的 rt-PCR 分析。在这些研究中，Wistar-Han 大鼠每隔 12 小时灌胃乙二醇 6 g/kg，共 7 天，或单次灌胃二甘酸 300 mg/kg。安乐死后采集肾组织，用福尔马林保存。组织切片用 RNAstorm FFPE RNA 分离试剂盒进行匀浆，分离 RNA。比较有二甘酸积聚和急性肾损伤的组与无二甘酸积聚或无毒性的组之间钠依赖性二羧酸转运体-1 mRNA 的表达。
与无肾二甘酸和无急性肾损伤的大鼠相比，有急性肾损伤和二甘酸积聚的大鼠肾组织中钠依赖性二羧酸转运体-1 mRNA 的表达显著升高。
大鼠接触乙二醇或二甘酸后发生急性肾损伤的可能性与增强将二甘酸摄取到肾细胞中的能力有关，这种能力与钠依赖性二羧酸转运体-1 有关。流行病学研究报告的人类乙二醇毒性的变异性也可能与二甘酸在组织中的摄取差异有关。
暴露于乙二醇或二甘酸后发生急性肾损伤的动物肾组织中钠依赖性二羧酸转运体-1 表达更高，二甘酸积聚更多，而无急性肾损伤的动物则没有。
