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Free Radic Biol Med. 2014 Jun;71:415-26. doi: 10.1016/j.freeradbiomed.2014.03.036. Epub 2014 Apr 1.

Involvement of Na/K-ATPase in hydrogen peroxide-induced activation of the Src/ERK pathway in LLC-PK1 cells.

Author information

1
Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Beijing, China.
2
Department of Physiology and Department of Pharmacology and Medicine, College of Medicine, University of Toledo, Toledo, OH 43614, USA.
3
Department of Physiology and Department of Pharmacology and Medicine, College of Medicine, University of Toledo, Toledo, OH 43614, USA. Electronic address: Zi-jian.Xie@utoledo.edu.

Abstract

We have shown that Na/K-ATPase interacts with Src. Here, we test the role of this interaction in H2O2-induced activation of Src and ERK. We found that exposure of LLC-PK1 cells to H2O2 generated by the addition of glucose oxidase into the culture medium activated Src and ERK1/2. It also caused a modest reduction in the number of surface Na/K-ATPases and in ouabain-sensitive Rb(+) uptake. These effects of H2O2 seem similar to those induced by ouabain, a specific ligand of Na/K-ATPase, in LLC-PK1 cells. In accordance, we found that the effects of H2O2 on Src and ERK1/2 were inhibited in α1 Na/K-ATPase-knockdown PY-17 cells. Whereas expression of wild-type α1 or the A420P mutant α1 defective in Src regulation rescued the pumping activity in PY-17 cells, only α1, and not the A420P mutant, was able to restore the H2O2-induced activation of protein kinases. Consistent with this, disrupting the formation of the Na/K-ATPase/Src complex with pNaKtide attenuated the effects of H2O2 on the kinases. Moreover, a direct effect of H2O2 on Na/K-ATPase-mediated regulation of Src was demonstrated. Finally, H2O2 reduced the expression of E-cadherin through the Na/K-ATPase/Src-mediated signaling pathway. Taken together, the data suggest that the Na/K-ATPase/Src complex may serve as one of the receptor mechanisms for H2O2 to regulate Src/ERK protein kinases and consequently the phenotype of renal epithelial cells.

KEYWORDS:

ERK; Free radicals; Hydrogen peroxide; Mutant; Na/K-ATPase; Src

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