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

• Published in: International journal of molecular sciences 2019-09, Vol.20 (19), p.4680
• Main Authors: Mizuno, Yu, Yamamotoya, Takeshi, Nakatsu, Yusuke, Ueda, Koji, Matsunaga, Yasuka, Inoue, Masa-Ki, Sakoda, Hideyuki, Fujishiro, Midori, Ono, Hiraku, Kikuchi, Takako, Takahashi, Masahiro, Morii, Kenichi, Sasaki, Kensuke, Masaki, Takao, Asano, Tomoichiro, Kushiyama, Akifumi
• Format: Article
• Language: English
• Subjects: Albumin; Albumins; Animals; Anti-Inflammatory Agents - therapeutic use; Body Weight - drug effects; Chemokine CCL2 - metabolism; Clinical trials; Collagen; Collagen - metabolism; Cytokines; Diabetes; Diabetes mellitus; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - immunology; Diabetic nephropathy; Drinking water; End-stage renal disease; Endoplasmic reticulum; Experimentation; Febuxostat - therapeutic use; Glucose; Glucose Intolerance - drug therapy; Glucose tolerance; Hyperglycemia; Hyperglycemia - drug therapy; Hyperuricemia; Hyperuricemia - drug therapy; IL-1β; Inflammation; Inhibitors; Insulin; Insulin resistance; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - metabolism; Interleukin 6; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Kidney diseases; Kidney Glomerulus - physiopathology; Metabolism; Mice; Mice, Inbred C57BL; Mice, Obese; Monocyte chemoattractant protein 1; mRNA; Nephropathy; Oxidative stress; Oxidative Stress - drug effects; Pathogenesis; Peptide Fragments - metabolism; Resistance factors; Risk analysis; Risk factors; Rodents; Uric acid; Uric Acid - blood; Xanthine oxidase; Xanthine Oxidase - antagonists & inhibitors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20194680

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.