STIMULATION BY EXTRACELLULAR ATP AND UTP OF THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE AND PROLIFERATION OF RAT RENAL MESANGIAL CELLS

被引:101
作者
HUWILER, A [1 ]
PFEILSCHIFTER, J [1 ]
机构
[1] UNIV BASEL,BIOZENTRUM,DEPT PHARMACOL,CH-4056 BASEL,SWITZERLAND
关键词
NUCLEOTIDE RECEPTOR; MITOGEN-ACTIVATED PROTEIN KINASE; MITOGEN-ACTIVATED PROTEIN KINASE KINASE; RENAL MESANGIAL CELLS; PROTEIN KINASE C;
D O I
10.1111/j.1476-5381.1994.tb17160.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 mu M, 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 P-2-receptor antagonist, suramin. 4 The protein kinase C activator 12-O-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. 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.
引用
收藏
页码:1455 / 1463
页数:9
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