title: Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation.
abstract: BACKGROUND
  It has been shown that the transcription factors activator protein (AP)-1 and nuclear factor (NF)-kappaB play a pivotal role in various renal diseases. We aimed to study their activations in chronic cyclosporine A (CsA) nephrotoxicity and evaluate the effect of magnesium (Mg) supplementation and blockade of the renin-angiotensin system (RAS), which are known to ameliorate CsA nephrotoxicity, on these transcription factors.
  
  
  METHODS
  CsA (15 mg/kg/day) was administered subcutaneously daily to rats maintained on a low-sodium diet for 7, 14, and 28 days. DNA-binding activities of AP-1 and NF-kappaB in renal cortex were determined by electrophoretic mobility shift assay.
  
  
  RESULTS
  DNA-binding activity of AP-1 and NF-kappaB started to increase at day 14 and further elevated at day 28 by CsA treatment. These activations were markedly attenuated when rats were maintained on a high-Mg diet. In contrast, angiotensin-converting enzyme inhibitor (ACEI) had no effect on CsA-induced AP-1 activation. CsA-induced activation of NF-kappaB was suppressed by ACEI at day 14, whereas such effect could not be observed at day 28.
  
  
  CONCLUSIONS
  Renal cortical AP-1 and NF-kappaB DNA binding were activated in chronic CsA nephrotoxicity. These activations were induced largely by means of RAS-independent mechanisms. It is suggested that prevention of CsA-induced DNA-binding activation of these transcription factors is at least in part responsible for the beneficial effects of Mg supplementation on CsA nephrotoxicity.
authors.affiliation: Department of Urology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Asai
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nakatani
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tamada
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kuwabara
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tashiro
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nakao
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Komiya
authors.forename: Mikio
authors.initials: M
authors.lastname: Okamura
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwao
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Miura
mesh_terms: D000818:Animals; D002908:Chronic Disease; D016572:Cyclosporine / Q000506:poisoning*; D004586:Electrophoresis; D007166:Immunosuppressive Agents / Q000506:poisoning*; D008274:Magnesium / Q000627:therapeutic use*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009399:Nephrons / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D016572:Cyclosporine; D008274:Magnesium