Ectopic overexpression of haem oxygenase-1 protects kidneys from carboplatin-mediated apoptosis

Yuh Mou Sue, Ching Feng Cheng, Ying Chou, Chih Cheng Chang, Pei Shan Lee, Shu Hui Juan

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Abstract

BACKGROUND AND PURPOSE: We previously reported that the activation of the nuclear factor of activated T-lymphocyte-3 (NFAT3) by carboplatin leads to renal apoptosis as a result of oxidative stress, which is reversed by N-acetylcysteine. Herein, we extend our previous work to provide evidence of the molecular mechanisms of haem oxygenase (HO)-1 in protecting against injury. EXPERIMENTAL APPROACH Protective mechanisms of HO-1 in carboplatin-mediated renal apoptosis were examined in C57BL/6 mice and rat renal tubular cells (RTC) with HO-1 induction or inactivation/knockdown. KEY RESULTS The HO-1, induced by cobalt protoporphyrin, protected against carboplatin-induced renal injury in vivo. This protection was decreased by an inhibitor of HO-1 action, tin protoporphyrin. In cultures of RTC, carboplatin-induced apoptosis was similarly affected by HO-1 overexpression or knockdown. Carboplatin-mediated NFAT3 activation and apoptosis involve activation of the signalling kinases, extracellular signal regulated kinase, Jun N-terminal kinase and protein kinase C, and such activation was reversed in cells overexpressing HO-1. Both products of the HO-1 reaction, CO and bilirubin, inhibited (by 30-40%) NFAT3 activation and production of the pro-apoptotic proteins Bcl-XS/Bax. Additionally, the activation of NFκB was markedly decreased by HO-1 induction. CONCLUSION AND IMPLICATIONS HO-1 and its reaction products show anti-apoptotic effects in carboplatin-mediated renal injury. A novel functional NFAT3 binding site identified in the rat HO-1 promoter region was involved in producing a 1.5-fold to 2.5-fold increase in HO-1 induction by carboplatin. Nevertheless, only HO-1 overexpression and activation prior to the carboplatin challenge provided protection against carboplatin-induced injury.

Original languageEnglish
Pages (from-to)1716-1730
Number of pages15
JournalBritish Journal of Pharmacology
Volume162
Issue number8
DOIs
Publication statusPublished - Apr 2011

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Keywords

  • apoptosis
  • carboplatin
  • ERK/JNK
  • haem oxygenase-1
  • nuclear factor of activated T-lymphocytes
  • PKC
  • reactive oxygen species
  • renal tubular cells

ASJC Scopus subject areas

  • Pharmacology

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