Use of xanthine oxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis in unilateral ureteral obstructive nephropathy.

Omori, Hiroki; Kawada, Noritaka; Inoue, Kazunori; Ueda, Yoshiyasu; Yamamoto, Ryohei; Matsui, Isao; Kaimori, Jyunya; Takabatake, Yoshitsugu; Moriyama, Toshiki; Isaka, Yoshitaka; Rakugi, Hiromi

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. Conclusion: 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.

XANTHINE oxidase; INFLAMMATION; FIBROSIS; KIDNEY diseases; HYPERURICEMIA; MACROPHAGES; OXIDATIVE stress; CYTOKINES

Clinical & Experimental Nephrology, 2012, Vol 16, Issue 4, p549

1342-1751

Academic Journal

10.1007/s10157-012-0609-3