Stimulation by extracellular ATP and UTP of the mitogen‐activated protein kinase cascade and proliferation of rat renal mesangial cells

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Abstract
1 Extracellular ATP and UTP have been reported to activate a nucleotide receptor that mediates phosphoinositide and phosphatidylcholine hydrolysis by phospholipases C and D, respectively. Here we report that ATP and UTP potently stimulate mesangial cell proliferation. 2 Both nucleotides stimulate phosphorylation and activation of mitogen-activated protein kinase and a biphasic phosphorylation of the up-stream mitogen-activated protein kinase kinase. 3 When added at 100 μm, ATPγS, UTP and ATP were the most potent activators of mitogen-activated protein kinase. βγ-imido-ATP was somewhat less active and ADP and 2-methylthio-ATP caused a weak induction of enzyme activity. Activation of mitogen-activated protein kinase by both ATP and UTP is dose-dependently attenuated by the P2-receptor antagonist, suramin. 4 The protein kinase C activator 12-0-tetradecanoylphorbol 13-acetate, but not the biologically inactive 4α-phorbol 12,13-didecanoate, increased mitogen-activated protein kinase activity in mesangial cells, suggesting that protein kinase C may mediate nucleotide-induced stimulation of mitogen-activated protein kinase. 5 Down-regulation of protein kinase C -α and-θ isoenzymes by 4 h or 8 h treatment with phorbol ester partially inhibited ATP- and UTP-triggered mitogen-activated protein kinase activation. Moreover, a 24 h treatment of mesangial cells with phorbol ester, a regimen that also causes depletion of protein kinase C-∍ did not further reduce the level of mitogen-activated protein kinase stimulation. 6 The specific protein kinase C inhibitor, CGP 41251, which displayed a selectivity for the Ca2+-dependent isoenzymes, as compared to the Ca2+-independent isoenzymes did not inhibit nucleotide-stimulated mitogen-activated protein kinase phosphorylation, thus implicating the involvement of a Ca2+-independent protein kinase C isoform. 7 In summary, these results suggest that ATP and UTP trigger the activation of the mitogen-activated protein kinase signalling cascade in mesangial cells and this may be responsible for the potent mitogenic activity of both nucleotides.

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