Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice

International Journal of Molecular Sciences

Hiraku Ono¹  Yasuka Matsunaga²  Yusuke Nakatsu²  Masa-Ki Inoue²  Takeshi Yamamotoya²  Koji Ueda²  Tomoichiro Asano²  Yu Mizuno²  Kenichi Morii³  Kensuke Sasaki³  Takao Masaki³  Masahiro Takahashi⁴  Akifumi Kushiyama⁴  Midori Fujishiro⁵  Takako Kikuchi⁶  Hideyuki Sakoda⁷ 

[1] Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan;Department of Medical Science, Graduate School of Medicine, University of Hiroshima, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan;Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan;Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose City, Tokyo 204-8588, Japan;Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan;Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6, Nihonbashi Bakurocho, Chuo-ku, Tokyo 103-0002, Japan;Division of Neurology, Respirology, Endocrinology, and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan;

关键词: diabetic kidney diseases;    xanthine oxidase;    glomerular damage;   

DOI  :  10.3390/ijms20194680

来源: DOAJ

【 摘 要 】

Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 μg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1β, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration.

【 授权许可】

Unknown