title: Losartan alleviates renal fibrosis by down-regulating HIF-1α and up-regulating MMP-9/TIMP-1 in rats with 5/6 nephrectomy.
abstract: BACKGROUND
  This study investigated the effects of losartan intervention on the expressions of hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in renal fibrosis in rats with 5/6 nephrectomy.
  
  
  METHODS
  Sprague Dawley rats were randomly divided into three groups. Rats in the losartan group were gavaged with losartan (33.3 mg/kg/day) from 1 week after 5/6 nephrectomy, and those in the sham group and the model group only received an equal volume of saline solution by gavage. Rats were sacrificed at the ends of the 4, 8 and 12 weeks, respectively. Urinary N-acetyl-glucosaminidase (NAG), 24-h urinary protein, serum cystatin C, blood urea nitrogen (BUN), and serum creatinine (Scr) levels were assessed. Kidney tissues were observed under light and electron microscope. The expressions of HIF-1α, transforming growth factor-β1 (TGF-β1), MMP-9, and TIMP-1 were determined by immunohistochemistry and Western blotting.
  
  
  RESULTS
  Twenty-four hour urinary protein, urinary NAG, serum cystatin C, BUN, and Scr levels in the model group were significantly higher than those in the sham group (p < 0.05), but losartan treatment improved these changes. The apparent glomerular sclerosis and tubulointerstitial fibrosis were also found in the model group, which were ameliorated by losartan. The expressions of HIF-1α, TGF-β1, MMP-9, and TIMP-1 were elevated and MMp-9/TIMP-1 ratio was lowered in the model group (p < 0.05), but losartan increased the expression of MMP-9 and MMp-9/TIMP-1 ratio (p < 0.05) and lessened the expressions of HIF-1α, TGF-β1, and TIMP-1 (p < 0.05).
  
  
  CONCLUSIONS
  Losartan may ameliorate renal fibrosis partly by down-regulating HIF-1α and up-regulating MMP-9/TIMP-1 in rats with 5/6 nephrectomy.
authors.affiliation: Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Fu
authors.forename: Yunman
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhouhui
authors.initials: Z
authors.lastname: Jin
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Cheng
authors.forename: Haishan
authors.initials: H
authors.lastname: Zhou
authors.forename: Peihao
authors.initials: P
authors.lastname: Yin
authors.forename: Wen
authors.initials: W
authors.lastname: Peng
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects*; D005355:Fibrosis / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000187:drug effects*; D009392:Nephrectomy / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis* / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9; D019808:Losartan