Abstract
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.
Highlights
Chronic kidney disease (CKD) is becoming more common[1], influencing 10% of the human popultion[2]
It is important to note that the identification of metabolites might be misleading, depending on the database; quantification of potential biomarkers is important in non-targeted metabolomics[26]
There was no obvious change in serum creatinine or blood urea nitrogen (BUN), renal tissues were certainly damaged by Pb (Fig. 2)
Summary
Chronic kidney disease (CKD) is becoming more common[1], influencing 10% of the human popultion[2]. 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 BUN13. The discovery of early biomarkers of low-level Pb-induced renal injury is necessary and important. One human serum metabolomics study showed that co-exposure to heavy metals disturbs lipid and amino acid metabolism[23]. Inhalation of Pb-containing PM2.5 particles mainly affects metabolic pathways such as amino acid metabolism, TCA cycle and nitrogen metabolism in rat urine and serum[24] In this regard, the interruption of amino acid metabolism is commonly found in heavy metal-induced toxicity[25]. Our study aims to explain the metformin-related renoprotection, and discover potential biomarkers for early diagnosis of low-level Pb-induced renal injury
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