Irsogladine maleate potentiates the effects of nitric oxide on activation of cAMP signalling pathways and suppression of mesangial cell mitogenesis
Irsogladine maleate potentiates the effects of nitric oxide on activation of cAMP signalling pathways and suppression of mesangial cell mitogenesis
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DOI：
10.1038/sj.bjp.0707255
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发表时间：
2007-06-01
影响因子：
7.3
通讯作者：
Kitamura, M.
中科院分区：
文献类型：
--
作者：
Yao, J.;Zhu, Y.;Kitamura, M.
背景和目的：一氧化氮（NO）缺乏是导致某些肾小球疾病恶化和进展的主要因素。提高NO利用率和潜力的药物具有肾保护作用。据报道，马来酸伊索拉定（IM）是一种抗溃疡药物，可通过NO依赖性机制改善胃血流量。因此，我们问IM是否以及如何与NO相互作用的肾小球系膜细胞。实验方法：系膜细胞暴露于IM和NO供体。cAMP信号通路的激活通过细胞内cAMP、VASP的磷酸化、cAMP反应元件（CRE）的激活和CRE调节蛋白的表达来评估。而NO供体S-亚硝基-N-乙酰青霉胺（SNAP）的抑制作用则明显增强。IM与NO在抑制丝裂原活化蛋白激酶活化、诱导缝隙连接蛋白connexin 43表达、增加细胞内cAMP和VASP磷酸化等方面具有协同作用。通过使用基于CRE-SEAP的报告系统，IM和SNAP协同激活cAMP应答元件（CRE）。用两种不同的NO供体，sGC激活剂Bay 41-2272和cGMP类似物8-溴-cGMP，通过IM诱导cAMP的类似激活。SNAP和IM对cAMP活化的作用由磷酸二酯酶3（PDE 3）和PDE 4抑制剂模拟。此外，IM显着增加了精氨酸诱导的iNOS的表达，产生的NO和激活CRE。结论和影响：IM通过协同激活cAMP途径大大增强了NO的作用。IM和NO的联合治疗可用于某些肾脏疾病。
Background and purpose: Deficiency in nitric oxide ( NO) is a major factor leading to deterioration and progression of certain glomerular diseases. Agents enhancing NO availability and potentiality are renoprotective. Irsogladine maleate (IM), an antiulcer drug, is reported to improve gastric blood flow via NO-dependent mechanisms. We, therefore, asked whether and how IM interacted with NO on glomerular mesangial cells.Experimental approach: Mesangial cells were exposed to IM and NO donors. Activation of cAMP signalling pathways was assessed by intracellular cAMP, phosphorylation of VASP, activation of the cAMP response element (CRE) and expression of CRE-regulated proteins.Key results: IM alone did not affect cell proliferation. However, it greatly enhanced the growth-inhibitory effect of NO donor S-nitroso-N-acetylpenicillamine (SNAP). IM acted synergistically with NO on suppression of mitogen-activated protein kinase activation, induction of gap junction protein connexin43, increase of intracellular cAMP, and phosphorylation of VASP. With the use of the CRE-SEAP-based reporting system, IM and SNAP cooperatively activated cAMP response elements (CRE). A similar activation of cAMP was induced by IM with two different NO donors, the sGC activator Bay 41-2272 and the cGMP analogue 8-bromo-cGMP. The effects of SNAP and IM on cAMP activation were mimicked by phosphodiesterase 3 (PDE3) and PDE4 inhibitors. In addition, IM markedly augmented cytokine-induced expression of iNOS, production of NO and activation of CRE.Conclusion and implications: The effects of NO were greatly potentiated by IM through synergistic activation of cAMP pathway. Combined therapy with IM and NO may be developed for certain renal diseases.