Inhibitors of cyclic nucleotide phosphodiesterase isozymes type-III and type-IV suppress mitogenesis of rat mesangial cells.
Inhibitors of cyclic nucleotide phosphodiesterase isozymes type-III and type-IV suppress mitogenesis of rat mesangial cells.
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DOI：
10.1172/jci118049
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发表时间：
1995-07
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影响因子：
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通讯作者：
K. Matoušovic;J. Grande;C. C. Chini-C.;E. Chini;T. Dousa
中科院分区：
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作者：
K. Matoušovic;J. Grande;C. C. Chini-C.;E. Chini;T. Dousa
我们研究了丝裂原活化蛋白激酶（MAPK）信号通路和camp -蛋白激酶（PKA）信号通路在调节系膜细胞（MC）有丝分裂发生中的相互作用，通过[3H]胸腺嘧啶掺入测定，添加或不添加EGF。福斯可林或二丁基cAMP强烈（60-70%）抑制[3H]胸腺嘧啶掺入MC。西洛他胺、利沙嗪酮或西洛他唑选择性cAMP-磷酸二酯酶（PDE）同位酶PDE- iii抑制剂抑制有丝分裂的程度与福斯可林和DBcAMP相似，并激活原位PKA，但cAMP水平未检测到升高。西洛他胺和西洛他唑在抑制系膜有丝分裂的效果比罗利普兰和denbufylline （PDE-IV同功酶抑制剂）高3倍以上，尽管PDE-IV在MC中的含量是PDE-III的2倍。另一方面，当与福斯克林孵育时，罗利普兰增强的cAMP积累量远高于西洛胺（10-100倍）。EGF增加MAPK活性（+300%）；抑制有丝分裂发生的PDE同工酶抑制剂也抑制MAPK。PDE同工酶抑制剂也抑制pdgf刺激的MC增殖。我们得出结论，cAMP抑制丝裂原依赖的mapk信号通路可能是由于pka催化的磷酸化而降低Raf-1的活性。此外，我们推测PDE-III代谢的cAMP池的少量增加与系膜增殖的调节密切相关。因此，PDE同工酶抑制剂有可能通过对信号通路的集中作用来抑制MC增殖。
We studied interactions between the mitogen-activated protein kinase (MAPK) signalling pathway and cAMP-protein kinase (PKA) signaling pathway in regulation of mitogenesis of mesangial cells (MC) determined by [3H]thymidine incorporation, with or without added EGF. Forskolin or dibutyryl cAMP strongly (by 60-70%) inhibited [3H]thymidine incorporation into MC. Cilostamide, lixazinone or cilostazol selective inhibitors of cAMP-phosphodiesterase (PDE) isozyme PDE-III, inhibited mitogenesis to similar extent as forskolin and DBcAMP and activated in situ PKA, but without detectable increase in cAMP levels. Cilostamide and cilostazol were more than three times more effective at inhibiting mesangial mitogenesis than rolipram and denbufylline, inhibitors of isozyme PDE-IV, even though PDE-IV was two times more abundant in MC than was PDE-III. On the other hand, when incubated with forskolin, rolipram-enhanced cAMP accumulation was far greater (10-100x) than with cilostamide. EGF increased MAPK activity (+300%); PDE isozyme inhibitors which suppressed mitogenesis also inhibited MAPK. PDE isozyme inhibitors also suppressed PDGF-stimulated MC proliferation. We conclude that cAMP inhibits the mitogen-dependent MAPK-signaling pathway probably by decreasing the activity of Raf-1 due to PKA-catalyzed phosphorylation. Further, we surmise that minor increase in the cAMP pool metabolized by PDE-III is intimately related to regulation of mesangial proliferation. Thus, PDE isozyme inhibitors have the potential to suppress MC proliferation by a focused effect upon signaling pathways.