Aristolochic acid-induced accumulation of methylglyoxal and Nε-(carboxymethyl)lysine: An important and novel pathway in the pathogenic mechanism for aristolochic acid nephropathy
Graphical abstract
Highlights
► Aristolochic acid (AA) caused nephropathy and rapidly developed into renal failure. ► Methylglyoxal and Nε-(carboxymethyl)lysine were linked with diabetic complications. ► We first revealed methylglyoxal was significantly higher in AA-treated mice kidney. ► Nε-(carboxymethyl)lysine was found in renal tubular region in AA-treated mice. ► GSH, necessary for MGO detoxification, was decreased in AA-treated mice kidney.
Introduction
Aristolochic acid nephropathy (AAN) is a type of progressive interstitial nephropathy that may lead to permanent, irreversible renal failure [1]. In Belgium, researchers reported that a group of patients who took Aristolochia fangchi to lose weight later developed renal failure [2]. Traditionally, Aristolochia has been used to treat arthritis, infections, inflammations, and tumors [3], [4]. It was once inappropriately used as a substitute for Stephania tetrandra, which led to Chinese herb nephropathy, later named AAN. Large amounts of aristolochic acid (AA) are found in Aristolochia, and AA has also been discovered in other plants. The Food and Drug Administration has advised the population to stop using botanical products containing AA. However, certain products containing AA remain available through online purchasing or because of contamination in herbal remedies [5]. Previously, the pathogenic mechanism for AAN was unclear, but several hypotheses on the mechanism exist; for example, direct cell toxicity [6], ischemia-induced tubular atrophy [7], and epithelial–mesenchymal transition [8]. Besides, antioxidant enzyme dysfunction and mitochondrial damage were observed in rats injected with AA [9].
Methylglyoxal (MGO) is a reactive intermediate metabolic of glycolysis and is also derived from amino acids and acetone [10]. Levels of MGO are elevated in serum and renal tissue in diabetic patients [11]. MGO is a highly cytotoxic compound and both the production and removal of MGO are involved in radical generation [10]. Also, MGO is detoxified through the glyoxalase system, which comprises glyoxalase I and II and uses a catalytic amount of GSH. The MGO also undergoes non-enzyme reactions that rapidly react with protein to form advanced glycation end products (AGEs), such as Nε-(carboxymethyl)lysine (CML). It is considered an indicative marker of diabetes mellitus complications [12].
Lou et al. showed that AA administered to rats caused the accumulation of fat droplets in renal tubular cells and systemic disturbance of free fatty acid [13]. Because fatty acid is a source of MGO [10], we were doubtful as to whether MGO also increased in the kidneys of AA mice. Moreover, Yu et al. discovered that exposing AA to human cells could induce oxidative DNA damage associated with GSH depletion [14]. GSH is a necessary component in metabolized MGO. Exposing AA to human promyelocytic leukemia cells (HL-60) caused GSH depletion, implying that MGO could be mass produced when cells are incubated with AA. Although MGO is such an important cytotoxic constituent, somehow no paper has yet referred to the relationship between MGO and AAN. The purpose of this study was to determine if a change occurs in MGO levels in the AAN model.
This study analyzed intra-renal MGO and CML levels in an AAN model as well as the relationship of the intra-renal GSH level and oxidative stress at the same time.
Section snippets
Chemicals
Citric acid, bovine serum album (BSA), creatinine, paraformaldehyde, sodium bisulfate, sodium heparin, MGO (40% aqueous solution), AA, sodium hydroxide (NaOH), ammonium chloride, 5,6-Diamino-2,4-dihydroxy-pyrimidine, xylene, and CML antibody were purchased from Sigma–Aldrich Fine Chemicals Inc. (St. Louis, MO, USA). An oxygen radical antioxidant capacity activity assay kit was obtained from Cell Biolabs Inc. (San Diego, CA, USA). A Bio-Rad protein assay kit was purchased from Bio-Rad (Richmond,
Successfully induced AAN model: renal function determination
Compared to control mice, mice in the AA group showed significantly increased levels of urinary protein (24.90 ± 2.41 (mg/dl)/Ucr (mg/dl) vs 8.40 ± 1.09 (mg/dl)/Ucr (mg/dl), p < 0.01). Microalbumin also increased significantly in mice injected with AA (31.39 ± 2.49 (mg/dl)/Ucr (mg/dl) vs 0.47 ± 0.07 (mg/dl)/Ucr (mg/dl), p < 0.01). Urinary creatinine levels decreased in AA mice (from 21.67 ± 1.30 (mg/dl)/Ucr (mg/dl) to 8.57 ± 0.42 (mg/dl)/Ucr (mg/dl)), but serum creatinine levels increased (from 0.08 ± 0.00 mg/dl
Discussion
Several laboratories develop AA models. After administering Wistar rats with 5 mg/kg/d of AA i.p. 5 d/week for 16 week, Zheng et al. sacrificed these rats at weeks 8, 12, 16, 20, and 24 [21]. They observed that, beginning in week 16, BUN and SCR increased significantly, with the appearance of proximal tubular epithelial cell swelling, luminal narrowing, and epithelial cell necrosis. Debelle et al. employed a low dose (1 mg/kg) and a high dose (10 mg/kg) of AA subcutaneous injection in Wistar rats
Acknowledgments
The authors would like to thank Han, Chuan-Hsiao, and Chang, Chia-hao for their useful advice on experimental techniques. This study was financially supported by the Shuang-Ho Medical Center–Taipei Medical University Joint Research Program (99TMU-SHH-04-4).
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These authors contributed equally to this work.