Open AccessOxidant Preconditioning Protects Human Proximal Tubular Cells against Lethal Oxidant Injury via p38 MAPK and Heme Oxygenase-1
Author(s) -
H. Thomas Lee,
Hua Xu,
Ayuko OtaSetlik,
Charles W. Emala
Publication year - 2003
Publication title -
american journal of nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.394
H-Index - 85
eISSN - 1421-9670
pISSN - 0250-8095
DOI - 10.1159/000072914
Subject(s) - cytoprotection , p38 mitogen activated protein kinases , mapk/erk pathway , heme oxygenase , ischemic preconditioning , protein kinase a , microbiology and biotechnology , signal transduction , kinase , hemin , cycloheximide , chemistry , pharmacology , biology , biochemistry , heme , medicine , oxidative stress , ischemia , protein biosynthesis , enzyme
Ischemic preconditioning protects the kidney from subsequent ischemic injury but the signal transduction pathways involved are unknown. Human proximal tubular (HK-2) cells were protected from injury with 2.5 mM H(2)O(2) by preconditioning with a single 15-min exposure to 500 microM H(2)O(2) followed by 16 h of recovery (oxidant preconditioning). To identify the signaling pathways involved in oxidant preconditioning, we utilized inhibitors of several signaling intermediates (MAPK/ERK kinase I, p38 mitogen-activated protein kinase (MAPK), protein kinase C and tyrosine kinase). A rapid but transient increase in p38 MAPK was observed following oxidant preconditioning and an inhibitor of p38 MAPK (SB203580) abolished the protection provided by oxidant preconditioning. Oxidant preconditioning was also associated with heat shock protein-27 phosphorylation (by p38 MAPK) and an increased synthesis of heme oxygenase-1 (HO-1). Stimulation or inhibition of HO-1 with hemin or Zn(II) protoporphyrin IX, respectively, mimicked or abolished oxidant preconditioning-mediated cytoprotection. Inhibitors of new protein synthesis (cycloheximide) and gene transcription (actinomycin D) also blocked the cytoprotection by oxidant preconditioning. We conclude that oxidant preconditioning protects HK-2 cells against more severe oxidant injury via activation of signaling pathways that include p38 MAPK and increased synthesis of HO-1.