title: DNA double-strand breaks induced intractable glomerular fibrosis in renal allografts.
abstract: BACKGROUND
  The relationship between DNA damage and glomerular fibrosis in renal allografts remains unclear.
  
  
  METHODS
  We examined renal allograft specimens from 35 patients in which DNA double-strand breaks (DSBs) and glomerular fibrosis were detected by phospho-histone H2A.X (γ-H2AX) expression and collagen (COL) types III, IV, and VI accumulation. We also examined the in vitro relationship between DNA damage and COL accumulation by mitomycin C (MMc)-induced DNA damage in human glomerular endothelial cells (HRGEc).
  
  
  RESULTS
  The γ-H2AX and COL type VI, which mainly accumulated in the subendothelial and mesangial regions, were positively correlated with the duration of the post-renal transplant (RT) period. In multiple regression analysis, the duration of the post-RT period and cg in the Banff '07 classification were identified as a significant predictor of COL type VI accumulation and γ-H2AX expression in the glomerular capillaries. In addition, the γ-H2AX-positive area was also identified as a predictor of glomerular accumulation of COL type VI. COL type VI was detected in the cytoplasm of the HRGEc, which was secreted into the supernatant after MMc stimulation with γ-H2AX expression. The number of γ-H2AX (-)/COL type VI (+) cells was inversely associated with the number of γ-H2AX (+)/COL type VI (-) cells during 24-h MMc treatment.
  
  
  CONCLUSIONS
  Our findings suggest that the long-term RT induces DSBs and HRGEc-secreted COL type VI accumulation in the glomerular capillaries, which might progress to intractable glomerular fibrosis.
authors.affiliation: Department of Nephrology, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsui
authors.affiliation: Department of Biochemistry I, School of Medicine, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sunatani
authors.affiliation: Department of Nephrology, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Hayashi
authors.affiliation: Department of Nephrology, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Okino
authors.affiliation: Department of Nephrology, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okushi
authors.affiliation: Department of Nephrology, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Mukai
authors.affiliation: Department of Nephrology, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Adachi
authors.affiliation: Department of Nephrology, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamaya
authors.affiliation: Department of Biochemistry I, School of Medicine, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Iwabuchi
authors.affiliation: Department of Nephrology, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan. h-yoko@kanazawa-med.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yokoyama
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D005260:Female; D005355:Fibrosis; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000633:toxicity; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C468783:H2AX protein, human; D006657:Histones; D016685:Mitomycin; D003094:Collagen
keywords: Collagen; DNA double-strand breaks; Endothelial dysfunction; Glomerular fibrosis; Renal allograft