Accumulation of methylglyoxal and d‐lactate in Pb‐induced nephrotoxicity in rats

Abstract

Lead (Pb) is an environmental pollutant associated with several diseases, such as nephrotoxicity. Methylglyoxal (MG) is a reactive dicarbonyl compound formed during glycolysis and reported to increase in kidney damage. Metformin is used as an MG scavenger in the clinic. In this study, we investigated the mechanism of Pb-induced renal injury and the effect of metformin on Pb-induced nephrotoxicity. Eighteen Wistar rats were randomly divided into three groups: control, Pb, and Pb + metformin groups. Pb (250 ppm) was administered in drinking water, and 50 mg/kg of metformin was co-administered orally. After 28 days, the levels of MG and its metabolite d-lactate in urine, serum and renal tissues were examined. The elevation of renal MG (56.86 ± 17.47 vs 36.40 ± 5.69, p < 0.01) and urinary d-lactate (0.68 ± 0.28 vs 0.32 ± 0.13, p < 0.01) was observed in Pb-exposed rats compared with those in control rats. After co-treatment with metformin, these phenomena were attenuated. In the present study, it was demonstrated for the first time that urinary d-lactate might serve as the candidate marker for Pb-induced nephrotoxicity in the clinic, and metformin might be a new therapeutic candidate for Pb poisoning.

Metabolic profiling of metformin treatment for low-level Pb-induced nephrotoxicity in rat urine

“…Quantitative data on these metaolites are shown in Table 1 . Value of urinary d -LA and l -LA were well-established in our previous studies 13 , 27 – 29 . We validated ALA, GAA, IAA and HA, and all quantitative methods had a good linear range, and acceptable precision, accuracy and matrix effect (Supplementary Tables S4 – 6 ).…”

“…In occupational Pb exposure, serum creatinine and blood urea nitrogen (BUN) are not suitable for evaluating renal dysfunction 11 , 12 . Our previous study demonstrated that rats with low-level Pb-induced nephrotoxicity had higher renal methylglyoxal and urinary d -lactate without increasing serum creatinine or BUN 13 . The elevation of serum creatinine and BUN may be advanced and not fully reversible in renal injury 14 .…”

“…Metformin had been contraindicated in patients with renal sufficiency 17 . However, our previous studies showed that it could attenuate renal injury via reduction of renal methylglyoxal 13 , 18 , 19 . In 2016, the U.S. Food and Drug Administration revised restrictions on metformin use in kidney impairment 20 .…”

Effect of prednisolone on glyoxalase 1 in an inbred mouse model of aristolochic acid nephropathy using a proteomics method with fluorogenic derivatization-liquid chromatography-tandem mass spectrometry

“…Urinary methylglyoxal amount from all of the mice were determined. The level of urinary methylglyoxal was determined by FD-HPLC according to a previously published method [20,[23][24][25]. In short, the methylglyoxal was incubated with 6-diamino-2,4-dihydroxypyrimidine sulfate (DDP) for 30 min at 60˚C and stopped with 0.01 M citric acid (pH 6.0).…”

Evaluation of the nephrotoxicity and safety of low-dose aristolochic acid, extending to the use of Xixin (Asurum), by determination of methylglyoxal and D-lactate

“…Methylglyoxal and D-lactate can be used to assess nephrotoxicity and play key roles in the progression of renal injury, including diabetic [11], gentamicin-induced [12], Pb-induced [13] and acute AA-induced nephropathy [14][15][16]. The highly reactive dicarbonyl groups of methylglyoxal denature proteins and nucleic acids; the resulting methylglyoxal-derived compounds are called advanced glycation end products (AGEs) [17].…”