Abstract

Methylglyoxal (MG) can cause protein glycation, resulting in cell damage and dysfunction. Accumulation of MG and its downstream metabolite Nε-(carboxyethyl)lysine (CEL) has been identified in several variations of nephropathy, including diabetic, hypertensive, and gentamicin-induced nephropathies. In this study, we investigated the effects of low-molecular-weight chitosan (lmw-chitosan) on MG-induced carbonyl stress in aristolochic acid-induced nephropathy. We used a buffer to investigate whether MG could be scavenged by lmw-chitosan in vitro. In addition, we also used a mouse model of aristolochic acid-induced nephropathy, which exhibits 12-fold greater accumulation of MG in the kidneys than that found in control animals, to examine whether lmw-chitosan could decrease MG levels in vivo. Examination of the binding of lmw-chitosan with MG in vitro demonstrated that the concentration of lmw-chitosan necessary to achieve 50% inhibition was 4.60 µg mL−1. Treatment with lmw-chitosan (500 mg kg−1 day−1 orally) for 14 days significantly decreased renal MG accumulation from 212.86 ± 24.34 to 86.15 ± 33.79 µg g−1 protein (p < 0.05) and CEL levels from 4.60 ± 0.27 to 2.84 ± 0.28 µmol µg−1 protein (p < 0.05) in the aristolochic acid-induced nephropathy model. These data suggest that lmw-chitosan might represent a novel treatment modality for MG-related diseases such as nephropathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1106-4) contains supplementary material, which is available to authorized users.

Highlights

  • Nephropathy can lead to the acquisition of end-stage renal disease, which is associated with major health problems

  • The lack of response in our animal model suggests that the glutathione level does not represent the primary target of lmw-chitosan; instead, we suggest that the reversal of MG and MG-derived CEL build-up by lmw-chitosan is the key mechanism of this treatment against nephropathy

  • We found that aristolochic acid nephropathy (AAN) mice treated with lmw-chitosan showed improved renal function, and that lmw-chitosan treatment significantly decreased renal MG accumulation and CEL levels

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Summary

Introduction

Nephropathy can lead to the acquisition of end-stage renal disease, which is associated with major health problems. Causes of nephropathy include medications or disease, as well as the toxicity associated with compounds such as the organic by-product methylglyoxal (MG). The pathogenesis of diabetic nephropathy and its associated complications are primarily related to MG and its downstream metabolites, which cause injury to the kidneys (Rabbani and Thornalley 2011). Only metformin has been approved as an effective MGreducing agent by the US Food and Drug Administration. This drug is not suggested for use in patients with renal insufficiency due to its toxicity.

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