Aristolochic acid-induced accumulation of methylglyoxal and Nε-(carboxymethyl)lysine: An important and novel pathway in the pathogenic mechanism for aristolochic acid nephropathy

• DOI: 10.1016/j.bbrc.2012.06.049
• Publication Date: 2012-06-18T07:32:06Z
• Authors: Yi-Chieh Li; Shin-Han Tsai; Shih-Ming Chen; Ya-Min Chang; Tzu-Chuan Huang; Yu-Ping Huang; Chen-Tien Chang; Jen-Ai Lee
• Keywords: 0301 basic medicine; Mice, Inbred C3H; Lysine; Creatine; Kidney; Pyruvaldehyde; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Animals; Aristolochic Acids; Nephritis, Interstitial; Female

Aristolochic acid, found in the Aristolochia species, causes aristolochic acid nephropathy (AAN) and can develop into renal failure. Methylglyoxal (MGO) is a highly cytotoxic compound generated from the metabolic process of glucose or fatty acids. It binds to proteins and forms N(ε)-(carboxymethyl)lysine (CML), which contributes to aging and diabetes mellitus complications. However, no relevant literature explores the relationship of MGO and CML with AAN. By injecting AA (10mg/kg BW) into C3H/He mice for 5 consecutive days, we successfully developed an AAN model and observed tubular atrophy with decreased renal function. Creatinine clearance also decreased from 10.32 ± 0.79 ml/min/kg to 2.19 ± 0.29 ml/min/kg (p<0.01). The concentration of MGO in kidney homogenates increased 12 × compared to the control group (from 18.23 ± 8.05 μg/mg of protein to 231.16 ± 17.57 μg/mg of protein, p<0.01), and CML was observed in the renal tubules of the mice by immunohistochemistry. Furthermore, compared to the control group, GSH levels decreased by 0.32 × (from 2.46 ± 0.41 μM/μg of protein to 0.78 ± 0.15 μM/μg of protein, p<0.01), whereas intra-renal antioxidant capacity decreased by 0.54×(from 6.82 ± 0.97 U to 3.71 ± 0.25 U; unit is equivalent to μM Trolox/mg of protein, p<0.01). In this study, we found that serious kidney damage induced by AA is related to an increase and accumulation of MGO and CML.