ERK promotes hydrogen peroxide-induced apoptosis through caspase-3 activation and inhibition of Akt in renal epithelial cells.
Reactive oxygen species, including hydrogen peroxide (H(2)O(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 H(2)O(2)-induced renal proximal tubular cells (RPTC) apoptosis. Exposure of RPTC to 1 mM H(2)O(2) 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 H(2)O(2)-induced apoptosis. In contrast, expression of constitutively active MEK1 enhanced H(2)O(2)-induced apoptosis. H(2)O(2) 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(2)O(2)-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.
Zhuang
Shougang
S
Dept. of Pharmaceutical Sciences, Medical Univ. of South Carolina, 280 Calhoun St., POB 250140, Charleston, SC 29425, USA. szhuang@lifespan.org
Yan
Yan
Y
Daubert
Rebecca A
RA
Han
Jiahuai
J
Schnellmann
Rick G
RG
D000256:Adenoviridae / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors*; D016877:Oxidants / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011817:Rabbits; D013778:Tetrazolium Salts; D013844:Thiazoles; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D002867:Chromones; D004791:Enzyme Inhibitors; D006657:Histones; D009025:Morpholines; D016877:Oxidants; D013778:Tetrazolium Salts; D013844:Thiazoles; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; C022616:thiazolyl blue