title: Febuxostat ameliorates diabetic renal injury in a streptozotocin-induced diabetic rat model.
abstract: BACKGROUND
  Oxidative stress and inflammation are known to play central roles in the development of diabetic nephropathy (DN). Febuxostat is a novel non-purine xanthine oxidase (XO)-specific inhibitor developed to treat hyperuricemia. In this study, we investigated whether febuxostat could ameliorate DN via renoprotective mechanisms such as alleviation of oxidative stress and anti-inflammatory actions.
  
  
  METHODS
  Male Sprague-Dawley rats were divided into three groups: a normal group, a diabetes group (DM group), and a febuxostat-treated diabetes group (DM+Fx group). We administered 5 mg/kg of febuxostat to experimental rats for 7 weeks and evaluated clinical and biochemical parameters and XO and xanthine dehydrogenase (XDH) activity in hepatic tissue. The degree of oxidative stress and extent of inflammation were evaluated from urine samples and renal tissue collected from each group.
  
  
  RESULTS
  Diabetic rats (DM and DM+Fx groups) had higher blood glucose and kidney weight relative to body weight than normal rats. Albuminuria was significantly reduced in febuxostat-treated diabetic rats compared with untreated diabetic rats. Quantitative analysis showed that hepatic XO and XDH activities were higher in the DM groups, but decreased after treatment with febuxostat. Urinary 8-OHdG concentrations and renal cortical nitrotyrosine also indicated reduced oxidative stress in the DM+Fx group relative to the DM group. The number of ED-1-stained cells in the glomerulus and tubule of diabetic renal tissue decreased in febuxostat-treated diabetic rats relative to that of non-treated diabetic rats. Diabetic rats also expressed higher transcript levels of inflammatory genes (E-selectin and VCAM-1), an inflammation-induced enzyme (COX-2), and inflammatory mediators (ED-1 and NF-κB) than control rats; expression of these genes was significantly reduced by treatment with febuxostat.
  
  
  CONCLUSIONS
  Febuxostat prevents diabetic renal injury such as albuminuria. This renoprotective effect appears to be due to attenuation of the inflammatory and oxidative effects of diabetes-induced renal damage through inhibition of XO and XDH activities.
authors.affiliation: Department of Nephrology, Seoul Red Cross Hospital, Seoul, Korea.
authors.forename: Hong-Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Jeong
authors.forename: Yang Gyun
authors.initials: YG
authors.lastname: Kim
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Moon
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Chun Gyoo
authors.initials: CG
authors.lastname: Ihm
authors.forename: Ji Youn
authors.initials: JY
authors.lastname: Sung
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Lee
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000419:Albuminuria; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D053331:Ectodysplasins / Q000187:drug effects / Q000378:metabolism; D000069465:Febuxostat; D006074:Gout Suppressants / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000633:toxicity; D013844:Thiazoles / Q000494:pharmacology*; D014968:Xanthine Dehydrogenase / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D000903:Antibiotics, Antineoplastic; D053331:Ectodysplasins; D006074:Gout Suppressants; D016328:NF-kappa B; D012333:RNA, Messenger; D013844:Thiazoles; D000069465:Febuxostat; D013311:Streptozocin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D003849:Deoxyguanosine