Xiao Li, Erika Abe, Yukako Yamakawa, Go Yoneda, Rika Fujino, Mami Yamashita, Yuumi Iida, Hirofumi Jono and Hideyuki Saito
Methotrexate (MTX) is currently utilized as a key drug in treatment of both malignant tumors and rheumatoid arthritis. However, MTX treatment is often associated with various side effects, such as pulmonary damage, hepatotoxicityand nephrotoxicity. Recent report also revealed that, even though total administered dosage of MTX was same, longer duration of MTX administration caused more severe adverse effect rather than short duration of its administration in clinical. Despite the importance of appropriate usage of MTX, the mechanism of kidney injury caused by the difference in duration of MTX administration remains still unknown. Here, we established animal models to determine the effect of administration duration on MTX-induced kidney injury and evaluated the significant factor and mechanism responsible for MTX caused-kidney injury. The dosage of MTX (25 mg/kg) were intraperitoneally injected by short-administration (25 mg/kg by 1 injection: Short-MTX) or long-administration (5 mg/kg by 5 injections: Long-MTX), respectively. In Long-MTX group, body weight, water intake, and urine volume were significantly decreased. Urea nitrogen and creatinine (CRE) in urine were obviously decreased in Long-MTX group, while blood urea nitrogen (BUN) and CRE in serum were increased in Long-MTX group. In addition, Long- MTX group showed the significant increase of both neutrophil gelatinase-associated lipocalin (N-gal) and kidney injury molecule 1 (Kim-1), kidney injury markers. Interestingly, renal MTX concentrations in Long-MTX group was higher than those in Short-MTX group. Moreover, 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), reliable oxidative stress markers, were significantly increased in Long-MTX group. Taken together, the present findings suggest that longer duration of MTX administration caused a higher MTX accumulation in kidney, thereby leading to kidney injury through an increase in oxidative stress.
