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

Sciprofile linkYu Mizuno, Yu Mizuno, Sciprofile linkTakeshi Yamamotoya, Takeshi Yamamotoya, Sciprofile linkYusuke Nakatsu, Yusuke Nakatsu, Sciprofile linkKoji Ueda, Koji Ueda, Sciprofile linkYasuka Matsunaga, Yasuka Matsunaga, Sciprofile linkMasa-Ki Inoue, Masa-Ki Inoue, Sciprofile linkHideyuki Sakoda, Hideyuki Sakoda, Sciprofile linkMidori Fujishiro, Midori Fujishiro, Sciprofile linkHiraku Ono, Hiraku Ono, Sciprofile linkTakako Kikuchi, Takako Kikuchi, Sciprofile linkMasahiro Takahashi, Masahiro Takahashi, Sciprofile linkKenichi Morii, Kenichi Morii, Sciprofile linkKensuke Sasaki, Kensuke Sasaki, Sciprofile linkTakao Masaki, Takao Masaki, Sciprofile linkTomoichiro Asano, Tomoichiro Asano, Sciprofile linkAkifumi Kushiyama Akifumi Kushiyama
Published: 21 September 2019
 by  MDPI
International Journal of Molecular Sciences , Volume 20; doi:10.3390/ijms20194680

Abstract: 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.
Keywords: Xanthine oxidase / Glomerular Damage / diabetic kidney diseases

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