title: Use of xanthine oxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis in unilateral ureteral obstructive nephropathy.
abstract: BACKGROUND
  Renal interstitial fibrosis is the common pathway in progressive renal diseases, where oxidative stress promotes inflammation and macrophage infiltration. Febuxostat is a novel nonpurine xanthine oxidase (XO)-specific inhibitor for treating hyperuricemia. While some reports suggest a relationship between hyperuricemia and chronic kidney disease (CKD), the renoprotective mechanism of an XO inhibitor in CKD remains unknown. Recent reports have focused on XO as a source of oxidative stress.
  
  
  METHODS
  Here, we investigate the potential of febuxostat to reduce fibrogenic and inflammatory responses in an established interstitial fibrosis model-unilateral ureteric obstruction (UUO). Male Sprague-Dawley rats were divided into three groups: sham-operated group, vehicle-treated UUO group, and febuxostat-treated UUO group.
  
  
  RESULTS
  Treatment with febuxostat diminished XO activity in obstructed kidneys, and suppressed nitrotyrosine, a marker of oxidative stress. Consequently, febuxostat inhibited early proinflammatory cytokine expression, followed by a reduction of interstitial macrophage infiltration. In addition, febuxostat suppressed transforming growth factor-β messenger RNA expression, thereby ameliorating smooth muscle alpha actin and type I collagen expression.
  
  
  CONCLUSIONS
  Our results provide evidence for the renoprotective action of febuxostat against the formation of interstitial fibrosis. A decrease in macrophage infiltration and interstitial fibrosis, along with a decrease of the oxidative stress marker, strongly suggests the existence of a causal relationship between them. Febuxostat may have therapeutic value in slowing or preventing interstitial fibrosis in patients with CKD.
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Omori
authors.forename: Noritaka
authors.initials: N
authors.lastname: Kawada
authors.forename: Kazunori
authors.initials: K
authors.lastname: Inoue
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Ueda
authors.forename: Ryohei
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Isao
authors.initials: I
authors.lastname: Matsui
authors.forename: Jyunya
authors.initials: J
authors.lastname: Kaimori
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Takabatake
authors.forename: Toshiki
authors.initials: T
authors.lastname: Moriyama
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
mesh_terms: D000818:Animals; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000069465:Febuxostat; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D009395:Nephritis, Interstitial / Q000473:pathology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D016207:Cytokines; D013844:Thiazoles; D016212:Transforming Growth Factor beta; D000069465:Febuxostat; D014969:Xanthine Oxidase