TY - JOUR
T1 - ERK promotes hydrogen peroxide-induced apoptosis through caspase-3 activation and inhibition of Akt in renal epithelial cells
AU - Zhuang, Shougang
AU - Yan, Yan
AU - Daubert, Rebecca A.
AU - Han, Jiahuai
AU - Schnellmann, Rick G.
PY - 2007/1
Y1 - 2007/1
N2 - 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.
AB - 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.
KW - Extracellular signaling-regulated kinase
KW - Histone
KW - Oxidative stress
KW - Phosphoinositide 3-kinase
KW - Renal proximal tubular cells
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U2 - 10.1152/ajprenal.00170.2006
DO - 10.1152/ajprenal.00170.2006
M3 - Article
C2 - 16885155
AN - SCOPUS:33846187694
SN - 1931-857X
VL - 292
SP - F440-F447
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 1
ER -