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

Chronic kidney disease is a worldwide problem, and Pb contamination is a potential risk factor. Since current biomarkers are not sensitive for the diagnosis of Pb-induced nephrotoxicity, novel biomarkers are needed. Metformin has both hypoglycaemic effects and reno-protection ability. However, its mechanism of action is unknown. We aimed to discover the early biomarkers for the diagnosis of low-level Pb-induced nephrotoxicity and understand the mechanism of reno-protection of metformin. Male Wistar rats were randomly divided into control, Pb, Pb + ML, Pb + MH and MH groups. Pb (250 ppm) was given daily via drinking water. Metformin (50 or 100 mg/kg/d) was orally administered. Urine was analysed by nuclear magnetic resonance (NMR)-based metabolomics coupled with multivariate statistical analysis, and potential biomarkers were subsequently quantified. The results showed that Pb-induced nephrotoxicity was closely correlated with the elevation of 5-aminolevulinic acid, d-lactate and guanidinoacetic acid in urine. After co-treatment with metformin, 5-aminolevulinic acid and d-lactate were decreased. This is the first demonstration that urinary 5-aminolevulinic acid, d-lactate and guanidinoacetic acid could be early biomarkers of low-level Pb-induced nephrotoxicity in rats. The reno-protection of metformin might be attributable to the reduction of d-lactate excretion.