title: Febuxostat Prevents Renal Interstitial Fibrosis by the Activation of BMP-7 Signaling and Inhibition of USAG-1 Expression in Rats.
abstract: BACKGROUND
  Renal interstitial fibrosis (RIF) is a common pathology associated with end-stage renal diseases. The activation of bone morphogenetic protein-7 (BMP-7)-Smad1/5/8 pathway seems to alleviate RIF. Uterine sensitization-associated gene-1 (USAG-1), a kidney-specific BMPs antagonist, is associated with the development and prognosis of several renal diseases. Febuxostat is a xanthine oxidase inhibitor that can attenuate the renal dysfunction of patients. The purpose of this study was to investigate the effects of febuxostat on renal fibrosis and to clarify the mechanisms underlying these effects.
  
  
  METHODS
  Rats were randomly divided into 6 groups termed a sham-operated group, a unilateral ureteral obstruction (UUO) group, 3 doses of febuxostat groups (low, intermediate and high doses) and a sham group treated with high-dose febuxostat. After 14 days, renal function, relative kidney weight, accumulation of glycogen and collagens were examined by different methods. Expression of α-SMA, transforming growth factor-β1 (TGF-β1), BMP-7 and USAG-1 was detected by western blotting and RT-PCR, respectively. The phosphorylation level of Smad1/5/8 was also quantified by western blotting.
  
  
  RESULTS
  The renal function was declined, and large amounts of glycogen and collagens were deposited in the kidneys of UUO rats compared with the rats in the sham group. Besides, expression of α-SMA and USAG-1 in these kidneys was elevated, and the TGF-β1 was also activated, while the BMP-7-Smad1/5/8 pathway was inhibited. Febuxostat reversed the changes stated earlier, exhibiting protective effects on RIF induced by UUO.
  
  
  CONCLUSIONS
  Febuxostat was able to attenuate RIF caused by UUO, which was associated with the activation of BMP-7-Smad1/5/8 pathway and the inhibition of USAG-1 expression in the kidneys of UUO rats.
authors.affiliation: Key Laboratory of Brain Diseases Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Cao
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Peng
authors.forename: Yaqian
authors.initials: Y
authors.lastname: Zhang
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Li
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.forename: Anzhou
authors.initials: A
authors.lastname: Xia
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000187:drug effects* / Q000502:physiology*; D000069465:Febuxostat / Q000494:pharmacology* / Q000627:therapeutic use*; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000473:pathology*; D008297:Male; D011506:Proteins / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D055419:Bone Morphogenetic Protein 7; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C473906:Sostdc1 protein, rat; D000069465:Febuxostat