Abstract
Prednisolone is involved in glucose homeostasis and has been used for treatment for aristolochic acid (AA) nephropathy (AAN), but its effect on glycolysis in kidney has not yet been clarified. This study aims to investigate the effect in terms of altered proteins after prednisolone treatment in a mice model of AAN using a proteomics technique. The six-week C3H/He female mice were administrated AA (0.5 mg/kg/day) for 56 days. AA+P group mice were then given prednisolone (2 mg/kg/day) via oral gavage for the next 14 days, and AA group mice were fed water instead. The tubulointerstitial damage was improved after prednisolone treatment comparing to that of AA group. Kidney homogenates were harvested to perform the proteomics analysis with fluorogenic derivatization-liquid chromatography-tandem mass spectrometry method (FD-LC-MS/MS). On the other hand, urinary methylglyoxal and D-lactate levels were determined by high performance liquid chromatography with fluorescence detection. There were 47 altered peaks and 39 corresponding proteins on day 14 among the groups, and the glycolysis-related proteins, especially glyoxalase 1 (GLO1), fructose-bisphosphate aldolase B (aldolase B), and triosephosphate isomerase (TPI), decreased in the AA+P group. Meanwhile, prednisolone decreased the urinary amount of methylglyoxal (AA+P: 2.004 ± 0.301 μg vs. AA: 2.741 ± 0.630 μg, p < 0.05), which was accompanied with decrease in urinary amount of D-lactate (AA+P: 54.07 ± 5.45 μmol vs. AA: 86.09 ± 8.44 μmol, p < 0.05). Prednisolone thus alleviated inflammation and interstitial renal fibrosis. The renal protective mechanism might be associated with down-regulation of GLO1 via reducing the contents of methylglyoxal derived from glycolysis. With the aid of proteomics analysis and the determination of methylglyoxal and its metabolite-D-lactate, we have demonstrated for the first time the biochemical efficacy of prednisolone, and urinary methylglyoxal and its metabolite-D-lactate might be potential biomarkers for AAN.
Highlights
Aristolochic acid nephropathy (AAN) was first introduced in 1993 [1]
Consistent with the finding by Vanherweghem et al, this study demonstrated the efficacy of prednisolone for AAN, which supported by improvement of tubular damage and collagen deposition, as well as immune markers
This study firstly suggested that prednisolone successfully alleviated inflammation and interstitial renal fibrosis and inhibited glycolysis, which led to reduce methylglyoxal, glyoxalase 1 (GLO1), and D-lactate, as well as other glycolysis-related proteins
Summary
Aristolochic acid nephropathy (AAN) was first introduced in 1993 [1]. After the Belgian women ingested slimming pills containing aristolochic acid (AA), their renal function dramatically decreased and managed by dialysis. AAI shows stronger nephrotoxicity than AAII in AAN because of the O-methoxy group at position C-8 of the nitrophenanthrene ring [4]. This structure of AAI facilitates AA interactions with DNA, and this AA-DNA adduct leads to cytotoxicity and carcinogenicity. Ma et al showed that low-dose prednisone (0.5 mg/kg) is effective at slowing the progression of AAN via the suppression of monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-β (TGF-β) activities [8]
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