Cellular defense against H2O2-induced apoptosis via MAP kinase–MKP-1 pathway

Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is an oxidative stress-inducible gene. In this study, we investigated signaling pathways involved in oxidative stress-induced MKP-1 expression and its role in apoptosis of rat mesangial cells. Northern and Western blot analyses showed that H2O2 induced expression of MKP-1 mRNA and protein in a dose-dependent manner, without affecting the stability of the transcript. H2O2 induced phosphorylation of extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun N-terminal kinase and consequently activated activator protein 1 (AP-1). Selective inhibitors of individual MAP kinases or a dominant-negative mutant of c-jun significantly suppressed the expression of MKP-1 by H2O2. Inhibition of MKP-1 by a protein tyrosine phosphatase inhibitor (vanadate) enhanced H2O2-triggered apoptosis. Consistently, transfection with a wild-type MKP-1, but not its catalytically inactive mutant MKP-1CS, attenuated H2O2-induced apoptosis. These data elucidate, for the first time, that induction of MKP-1 by H2O2 is mediated by the MAP kinase–AP-1 pathway and that the induced MKP-1 is involved in cellular defense against oxidative stress-induced apoptosis of mesangial cells.