ERK promotes hydrogen peroxide-induced apoptosis through caspase-3 activation and inhibition of Akt in renal epithelial cells

Shougang Zhuang, Yan Yan, Rebecca A. Daubert, Jiahuai Han, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

Abstract

Reactive oxygen species, including hydrogen peroxide (H2O 2), are generated during ischemia-reperfusion and are critically involved in acute renal failure. The present studies examined the role of the extracellular signal-regulated kinase (ERK) pathway in H2O 2-induced renal proximal tubular cells (RPTC) apoptosis. Exposure of RPTC to 1 mM H2O2 resulted in apoptosis and activation of ERK1/2 and Akt. Pretreatment with the specific MEK inhibitors, U0126 and PD98059, or adenoviral infection with a construct that encodes a negative mutant of MEK1, protected cells against H2O2-induced apoptosis. In contrast, expression of constitutively active MEK1 enhanced H 2O2-induced apoptosis. H2O2 induced activation of caspase-3 and phosphorylation of histone H2B at serine 14, a posttranslational modification required for nuclear condensation, which also were blocked by ERK1/2 inhibition. Furthermore, blockade of ERK1/2 resulted in an increase in Akt phosphorylation and blockade of Akt potentiated apoptosis and diminished the protective effect conferred by ERK inhibition in H 2O2-treated cells. Although Z-DEVD-FMK, a caspase-3 inhibitor, was able to inhibit histone H2B phosphorylation and apoptosis, it did not affect ERK1/2 phosphorylation. We suggest that ERK elicits apoptosis in epithelial cells by activating caspase-3 and inhibiting Akt pathways and elicits nuclear condensation through caspase-3 and histone H2B phosophorylation during oxidant injury.

Original languageEnglish (US)
Pages (from-to)F440-F447
JournalAmerican Journal of Physiology - Renal Physiology
Volume292
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

Keywords

  • Extracellular signaling-regulated kinase
  • Histone
  • Oxidative stress
  • Phosphoinositide 3-kinase
  • Renal proximal tubular cells

ASJC Scopus subject areas

  • Physiology
  • Urology

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