Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation.
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.
Asai
Toshihiro
T
Department of Urology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.
Nakatani
Tatsuya
T
Tamada
Satoshi
S
Kuwabara
Nobuyuki
N
Yamanaka
Shinya
S
Tashiro
Koichiro
K
Nakao
Takafumi
T
Komiya
Toshiyuki
T
Okamura
Mikio
M
Kim
Shokei
S
Iwao
Hiroshi
H
Miura
Katsuyuki
K
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*
D007166:Immunosuppressive Agents; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D016572:Cyclosporine; D008274:Magnesium