title: Acquired resistance to rechallenge injury in rats that recovered from mild renal damage induced by uranyl acetate: accelerated proliferation and hepatocyte growth factor/c-Met axis.
abstract: BACKGROUND
  Rats that recovered from mild proximal tubule (PT) injury without renal dysfunction by subtoxic insult, developed partial resistance to subsequent nephrotoxic insult. This partial resistance was associated with reduced renal dysfunction and accelerated PT cell proliferation compared with vehicle treatment as the first insult. Here we assessed the role and potential mechanisms of accelerated PT proliferation in this acquired resistance model.
  
  
  METHODS
  Rats at 14 days after recovering from prior mild renal damage induced by 0.2 mg/kg uranyl acetate (UA) (subtoxic dose) were rechallenged with 4 mg/kg UA (nephrotoxic dose) to establish the acquired resistance model. Cell cycle was inhibited by colchicine to examine the contribution of accelerated PT cell proliferation evaluated by in vivo bromodeoxyuridine (BrdU) labeling on acquired resistance to subsequent nephrotoxic insult. Hepatocyte growth factor (HGF)/c-Met axis and other related factors of cell cycle were analyzed.
  
  
  RESULTS
  The acquired resistance to rechallenge injury with nephrotoxic dose of UA in rats recovered from mild renal injury was associated with an earlier increase in BrdU-positive PT cells, accelerated upregulation of HGF mRNA, c-Met mRNA/protein, cyclin D1, phospho-Rb and an earlier phenotypic change of PT cells. Colchicine inhibited PT cell proliferation, reduced the upregulated cyclin D1 and phospho-Rb in the kidney, completely abolishing acquired resistance.
  
  
  CONCLUSIONS
  Cell cycle progression with upregulated renal HGF/c-Met axis may contribute to the accelerated recovery from acute renal failure in rats that recovered from prior mild renal damage, followed by nephrotoxic insult, resulting in partial acquired resistance.
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan. yf0516@hama-med.ac.jp.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fujigaki
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Sakakima
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujikura
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
authors.forename: Akashi
authors.initials: A
authors.lastname: Togawa
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Huang
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hishida
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D004351:Drug Resistance; D017228:Hepatocyte Growth Factor / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000502:physiology / Q000503:physiopathology; D008297:Male; D009942:Organometallic Compounds / Q000009:adverse effects*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009942:Organometallic Compounds; C005460:uranyl acetate; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met