title: Fimasartan, a Novel Angiotensin-Receptor Blocker, Protects against Renal Inflammation and Fibrosis in Mice with Unilateral Ureteral Obstruction: the Possible Role of Nrf2.
abstract: OBJECTIVE
  A newly developed angiotensin II receptor blocker, fimasartan, is effective in lowering blood pressure through its action on the renin-angiotensin system. Renal interstitial fibrosis, believed to be due to oxidative injury, is an end-stage process in the progression of chronic kidney disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to regulate cellular oxidative stress and induce expression of antioxidant genes. In this study we investigated the role of Nrf2 in fimasartan-mediated antioxidant effects in mice with renal fibrosis induced by unilateral ureteral obstruction (UUO).
  
  
  METHODS
  UUO was induced surgically in mice, followed by either no treatment with fimasartan or the intraperitoneal administration of fimasartan (3 mg/kg/day). On day 7, we evaluated the changes in the renin-angiotensin system (RAS) and the expression of Nrf2 and its downstream antioxidant genes, as well as renal inflammation, apoptosis, and fibrosis in the obstructed kidneys. The effect of fimasartan on the Nrf2 pathway was also investigated in HK-2 cells stimulated by tumor necrosis factor-α.
  
  
  RESULTS
  The mice with surgically induced UUO showed increased renal inflammation and fibrosis as evidenced by histopathologic findings and total collagen content in the kidney. These effects were attenuated in the obstructed kidneys of the fimasartan-treated mice. Fimasartan treatment inhibited RAS activation and the expression of Nox1, Nox2, and Nox4. In contrast, fimasartan upregulated the renal expression of Nrf2 and its downstream signaling molecules (such as NQO1; HO-1; GSTa2 and GSTm3). Furthermore, it increased the expression of antioxidant enzymes, including CuSOD, MnSOD, and catalase. The fimasartan-treated mice had significantly less apoptosis on TUNEL staining, with decreased levels of pro-apoptotic protein and increased levels of anti-apoptotic protein. In the HK-2 cells, fimasartan treatment inhibited RAS activation, decreased expression of mitogen-activated protein kinases (MAPKs), and upregulated the Nrf2 pathway.
  
  
  CONCLUSIONS
  These results suggest that fimasartan has beneficial effects in reducing renal oxidative stress, inflammation, and fibrosis. Possible mechanisms to explain these effects are inhibition of RAS and MAPKs and upregulation of Nrf2 signaling, with subsequent induction of antioxidant pathways.
authors.affiliation: 1. Division of of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea.
authors.forename: Soojeong
authors.initials: S
authors.lastname: Kim
authors.affiliation: 2. Division of of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea.
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: 2. Division of of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea.
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Yoon
authors.affiliation: 1. Division of of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Chung
authors.affiliation: 1. Division of of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea.
authors.forename: Bum Soon
authors.initials: BS
authors.lastname: Choi
authors.affiliation: 1. Division of of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea.
authors.forename: Cheol Whee
authors.initials: CW
authors.lastname: Park
authors.affiliation: 2. Division of of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea.
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Shin
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D005355:Fibrosis; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D009393:Nephritis / Q000517:prevention & control*; D011743:Pyrimidines / Q000627:therapeutic use*; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction; D013599:Systole / Q000187:drug effects; D013777:Tetrazoles / Q000627:therapeutic use*; D014517:Ureteral Obstruction
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011743:Pyrimidines; D013777:Tetrazoles; C558933:fimasartan
keywords: MAPKs; fimasartan; nuclear factor erythroid-2-related factor 2; oxidative stress; renin-angiotensin system