title: Inhibition of p38 mitogen-activated protein kinases attenuates renal interstitial fibrosis in a murine unilateral ureteral occlusion model.
abstract: OBJECTIVE
  Cellular hypoxia has been proposed as a major factor contributing to the pathogenesis of chronic renal injury. Much of our understanding of how mitogen-activated protein kinases (MAPK) signaling promotes renal fibrosis has been based on cell culture studies. Therefore, we used the unilateral ureteral occlusion (UUO) model to further elucidate the role of the p38 MAPK pathway in renal interstitial fibrosis induced by hypoxia.
  
  
  METHODS
  In the present study, 24 male mice were randomized into the following three groups (n=8 each): Sham group (DMSO solution), UUO group (UUO+DMSO solution) and UP group (UUO+p38 inhibitor). The model of UUO was conducted using an established procedure described previously. Histological changes in renal tubular interstitium were observed with hematoxylin-eosin (HE) and Masson's trichrome. The protein levels of hypoxia inducible factor-1α (HIF-1α)、transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) and collagen type I were analyzed by western blotting and immunohistochemistry at 2weeks.
  
  
  RESULTS
  Increased expression of hypoxia inducible factor-1α (HIF-1α) in UUO mice confirmed the existence of hypoxia in renal interstitial. Hypoxia result in tubulointerstitial fibrosis via the molecular activation of connective tissue growth factor (CTGF). p38 inhibitor administration markedly downregulates the protein of connective tissue growth factor (CTGF) and collagen type I expression induced by hypoxia.
  
  
  CONCLUSIONS
  An increase in p38 MAPK activation is induced by hypoxia. The hypoxia up-regulates the protein connective tissue growth factor (CTGF) and collagen I expression in a p38-dependent manner.
authors: Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
authors: Fang
authors: F
authors: Gao
authors: Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
authors: Yanping
authors: Y
authors: Wang
authors: Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
authors: Shulin
authors: S
authors: Li
authors: Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
authors: Zhuojun
authors: Z
authors: Wang
authors: Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
authors: Caixia
authors: C
authors: Liu
authors: Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China; Department of Internal Medicine and Diagnostics, Xuzhou Medical University, Xuzhou 221002, China. Electronic address: sundong126@yahoo.com.
authors: Dong
authors: D
authors: Sun
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000032:analysis; D055513:Connective Tissue Growth Factor / Q000032:analysis; D004195:Disease Models, Animal; D005355:Fibrosis; D000860:Hypoxia / Q000150:complications*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007093:Imidazoles / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Interstitial fibrosis; Kidney; Unilateral ureteral occlusion; p38 MAPK