Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation

Transplantation. 2003 Apr 15;75(7):1040-4. doi: 10.1097/01.TP.0000057242.96219.AF.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • Cyclosporine / poisoning*
  • Electrophoresis
  • Immunosuppressive Agents / poisoning*
  • Magnesium / therapeutic use*
  • Male
  • NF-kappa B / metabolism*
  • Nephrons / drug effects*
  • Nephrons / pathology
  • Nephrons / physiopathology*
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factor AP-1 / metabolism*

Substances

  • Immunosuppressive Agents
  • NF-kappa B
  • Transcription Factor AP-1
  • Cyclosporine
  • Magnesium