Aristolochic acid-induced accumulation of methylglyoxal and Nε-(carboxymethyl)lysine: an important and novel pathway in the pathogenic mechanism for aristolochic acid nephropathy.
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.
School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250 Wuxing St., Taipei 11031, Taiwan, ROC.
Yi-Chieh
YC
Li
Shin-Han
SH
Tsai
Shih-Ming
SM
Chen
Ya-Min
YM
Chang
Tzu-Chuan
TC
Huang
Yu-Ping
YP
Huang
Chen-Tien
CT
Chang
Jen-Ai
JA
Lee
D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D003401:Creatine / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D011765:Pyruvaldehyde / Q000378:metabolism*
D034341:Aristolochic Acids; C048496:N(6)-carboxymethyllysine; D011765:Pyruvaldehyde; C000228:aristolochic acid I; D008239:Lysine; D003401:Creatine