p38 Mitogen-activated protein kinase protects glomerular epithelial cells from complement-mediated cell injury
p38 Mitogen-activated protein kinase protects glomerular epithelial cells from complement-mediated cell injury
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DOI：
10.1152/ajprenal.00100.2003
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发表时间：
2003-10-01
影响因子：
4.2
通讯作者：
Takano, T
中科院分区：
文献类型：
--
作者：
Aoudjit, L;Stanciu, M;Takano, T
在膜性肾病大鼠被动型Heymann肾炎(PHN)模型中，补体C5b-9可引起肾小球上皮细胞(GEC)亚溶解损伤。我们先前的研究表明，C5b-9的亚溶体浓度在GEC中触发了多种生物学事件。在目前的研究中，我们证明了补体激活GEC中的p38MAPK，并阐述了p38在补体介导的细胞损伤中的作用。当补体刺激培养的大鼠肾小管上皮细胞时，p38激酶活性和磷酸化水平与对照组相比增加了2.4倍。用p38抑制剂治疗可显著增强补体介导的细胞毒作用。相反，当p38上游的转化生长因子-β-激活激酶1(TAK1)的结构性活性突变体以可诱导的方式在GEC中表达时，与未诱导的细胞相比，细胞毒性显著降低。P38抑制剂可阻断TAK1表达的保护作用。通过与培养细胞的类比，p38活性也在PHN大鼠的肾小球中增加，p38抑制剂FR-167653治疗增加了蛋白尿。补体诱导MAPK相关蛋白激酶2(MAPKAPK-2)的磷酸化，MAPKAPK-2是GEC中p38下游的一种激酶。热休克蛋白(HSP27)是MAPKAPK-2的细胞骨架相互作用底物。野生型HSP27的过表达，而不是非磷酸化突变体，显著减少了补体介导的GEC损伤。综上所述，补体可激活体外培养的肾小球内皮细胞和PHN大鼠肾小球中的p38MAPK。P38MAPK的激活可能对补体介导的GEC损伤具有细胞保护作用。HSP27的磷酸化可能介导这种细胞保护。
In the passive Heymann nephritis (PHN) model of rat membranous nephropathy, complement C5b-9 causes sublytic injury of glomerular epithelial cells (GEC). We previously showed that sublytic concentration of C5b-9 triggers a variety of biological events in GEC. In the current study, we demonstrate that complement activates p38 MAPK in GEC and address the role of p38 in complement-mediated cell injury. When cultured rat GEC were stimulated with complement, p38 kinase activity and phosphorylation were increased by similar to2.4- fold, compared with control. Treatment with p38 inhibitors significantly augmented complement-mediated cytotoxicity. In contrast, when the constitutively active mutant of transforming growth factor-beta-activated kinase 1 (TAK1), a kinase upstream of p38, was expressed in GEC in an inducible manner, cytotoxicity was significantly reduced, compared with uninduced cells. p38 inhibitors abolished the protective effect of TAK1 expression. By analogy to cultured cells, p38 activity was also increased in glomeruli from rats with PHN and treatment with the p38 inhibitor FR-167653 increased proteinuria. Complement induced phosphorylation of MAPK-associated protein kinase-2 (MAPKAPK-2), a kinase downstream of p38 in GEC. Heat shock protein (HSP27) is a cytoskeleton-interacting substrate of MAPKAPK-2. Overexpression of the wildtype HSP27, but not a non-phosphorylatable mutant, markedly reduced complement-mediated GEC injury. In summary, complement activates p38 MAPK in GEC in vitro and in glomeruli from rats with PHN. The activation of p38 MAPK appears to be cytoprotective for GEC against complement-mediated GEC injury. Phosphorylation of HSP27 may mediate this cytoprotection.