Premium
Ectopic overexpression of haem oxygenase‐1 protects kidneys from carboplatin‐mediated apoptosis
Author(s) -
Sue YuhMou,
Cheng ChingFeng,
Chou Ying,
Chang ChihCheng,
Lee PeiShan,
Juan ShuHui
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01189.x
Subject(s) - carboplatin , kinase , biology , apoptosis , microbiology and biotechnology , cancer research , biochemistry , cisplatin , genetics , chemotherapy
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.