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. 1994 Dec;113(4):1455–1463. doi: 10.1111/j.1476-5381.1994.tb17160.x

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

A Huwiler 1, J Pfeilschifter 1
PMCID: PMC1510501  PMID: 7889302

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 microM, ATP gamma S, UTP and ATP were the most potent activators of mitogen-activated protein kinase. beta gamma-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 4 alpha-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 -alpha and -delta 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-epsilon did not further reduce the level of mitogen-activated protein kinase stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

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