Extracellular adenosine triphosphate protects oxidative stress-induced increase of p21WAF1/Cip1 and p27Kip1 expression in primary cultured renal proximal tubule cells: Role of PI3K and Akt signaling

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Lee, Yun Jung; Lee, Jang-Hern; Han, Ho Jae
Issue Date
John Wiley & Sons
J Cell Physiol 209(3):802–810
Oxidative stress, the result of cellular production of reactive oxygen species (ROS), has been implicated in causing many renal
diseases. Adenosine triphosphate (ATP) is an important extracellular signal in the regulation of many intracellular processes in
normal tubular cells as well as in the pathogenesis of cell injury. This study investigated the effect of ATP onH2O2-induced increase
of cyclin kinase inhibitors (CKI) expression and its related signal molecules in primary cultured renal proximal tubule cells (PTCs).
H2O2 inhibited DNA synthesis in a concentration- (>50 mM) and time-dependent manner (>2 h), as determined by thymidine and
BrdU incorporation, and by increase in the p21WAF/Cip1 and p27Kip1 expression levels. In contrast, ATP increased the level of
thymidine, BrdU incorporation (>10 5 M), and decreased the p21WAF/Cip1 and p27Kip1 expression levels, suggesting that ATP has a
protective effect againstH2O2-induced oxidative damage. Suramin, reactive blue 2 (RB-2), MRS 2159, and MRS 2179 did block the
reversing effect of ATP. In addition, AMP-CPP or 2-methylthio-ATP blockedH2O2-induced inhibition ofDNA synthesis, suggesting
all these P2 purinoceptors may be potentially involved. ATP-induced stimulation of DNA synthesis was blocked by
phosphatidylinositol 3-kinase (PI3K) and Akt inhibitors. These results suggest the involvement of P2 purinoceptors-mediated
PI3K/Akt signal pathway in the protective effect of ATP againstH2O2-induced oxidative damage. Indeed, pre-treatment with PI3K or
Akt inhibitors did not protect H2O2-induced lipid peroxide (LPO) production and inhibition of thymidine incorporation. In
conclusion, ATP, in part, blocked H2O2-induced increase of p21WAF1/Cip1 and p27Kip1 expression through PI3K and Akt signal
pathway in renal PTCs.
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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