Nitric oxide modulates mechanical strain-induced activation of p38 MAPK in mesangial cells
Nitric oxide modulates mechanical strain-induced activation of p38 MAPK in mesangial cells
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DOI：
10.1152/ajprenal.2000.279.2.f243
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发表时间：
2000-08-01
影响因子：
4.2
通讯作者：
Scholey, JW
中科院分区：
文献类型：
--
作者：
Ingram, AJ;James, L;Scholey, JW
肾小球系膜细胞(MC)生长在细胞外基质(ECM)蛋白包被的平板上，被拉伸、增殖并产生ECM，在体内概括了对肾小球毛细血管压力(PGC)升高的反应。菌株的转导涉及丝裂原活化蛋白激酶(MAPK)，我们已经证明在MC中p38MAPK是被菌株激活的。由于体内研究表明，残留肾脏中的一氧化氮(NO)在不降低PGC的情况下限制了肾小球的损伤，因此我们研究了NO是否减弱了牵张诱导的MC中p38的激活。P38活性随拉伸强度的增加而增加，在227 kpa真空度下10min时达到最大值。通过免疫荧光显微镜观察和迁移率改变分析，循环菌株增加了磷酸化p38的核转位和核因子-kappa B(核因子-kappa B)共同序列的核蛋白结合。这两个事件在很大程度上被p38抑制剂SB-203580所废除。NO供体3-吗啉-吡喃亚胺、S-亚硝基-N-乙酰青霉胺和稳定的cGMP类似物8-溴鸟苷3‘，5’-环单磷酸可抑制p38的激活和核转位。因此，菌株诱导p38活性和转位到细胞核，并依赖p38增加核蛋白与核因子-kappa B的结合，这一途径被NO供体或cGMP类似物减弱。
Mesangial cells (MC), grown on extracellular matrix (ECM) protein-coated plates and stretched, proliferate and produce ECM, recapitulating in vivo responses to increased glomerular capillary pressure (Pgc). Transduction of strain involves mitogen-activated protein kinases (MAPK), and we have shown that p38 MAPK is activated by strain in MC. Because in vivo studies show that nitric oxide (NO) in the remnant kidney limits glomerular injury without reducing Pgc, we studied whether NO attenuated stretch-induced p38 activation in MC. Increasing p38 activation occurred with increasing stretch, maximally at 10 min at 227-kPa vacuum. Cyclic strain increased nuclear translocation of phosphorylated p38 by immunofluorescent microscopy and nuclear protein binding to nuclear factor-kappa B (NF-kappa B) consensus sequences by mobility shift assay. Both events were largely abrogated by the p38 inhibitor SB-203580. The NO donors 3-morpholinosydnonimine, S-nitroso-N-acetylpenicillamine, and 8-bromoguanosine 3', 5'-cyclic monophosphate, a stable cGMP analog, prevented p38 activation and nulcear translocation. Thus strain induces p38 activity and translocation to the nucleus and p38-dependent increases in nuclear protein binding to NF-kappa B. This pathway is attenuated by the NO donors or a cGMP analog.