RAPID AND DELAYED P42/P44 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION BY NITRIC OXIDE : THE ROLE OF CYCLIC GMP AND TYROSINE PHOSPHATASE INHIBITION

摘要: The exposure of rat mesangial cells to cytokines promoted activation the p42/p44 mitogen-activated protein kinase (MAPK). We identified a rapid and delayed phase MAPK with distinctive activity increases at 5 15 min 24 h. Rapid late were attenuated by redox-modulating agent N -acetylcysteine. Specifically, late-phase coincided endogenous nitric oxide (NO) generation in turn was suppressed NO synthase-blocking compounds diphenyliodonium or nitroarginine methyl ester. By using NO-liberating agents such as S -nitrosoglutathione 3-morpholinosydnonimine, we investigated intermediary signaling elements promoting activation. Early transient soluble guanylyl cyclase-blocking 1 H -(1,2,4)-oxdiazolo-(4,3-α)-6-bromoquinoxazin-1-one (NS 2028) and, moreover, mimicked lipophilic cyclic GMP (cGMP) analogue 8-bromo-cGMP. In contrast, NO-mediated achieved within hours unrelated cGMP signaling. Late persistent activation, induced donors endogenously generated NO, found association inhibition phosphatase activity. vitro dephosphorylation activated immunoprecipitated cytosolic phosphatases sensitive readdition be inhibited cytosol -nitrosoglutathione-stimulated cells. Also, that had been exposed for h revealed blocked activity, which successfully synthase inhibitor ester therefore, mediated. Conclusively, affects twofold: is mediated, whereas transmitted via tyrosine dephosphorylation.