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细胞外信号调节激酶(ERK)的激活可加速肾小管上皮细胞的修复,而抑制缺血/再灌注损伤后的纤维化进程。

Activation of ERK accelerates repair of renal tubular epithelial cells, whereas it inhibits progression of fibrosis following ischemia/reperfusion injury.

作者信息

Jang Hee-Seong, Han Sang Jun, Kim Jee In, Lee Sanggyu, Lipschutz Joshua H, Park Kwon Moo

机构信息

Department of Anatomy, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea; Cardiovascular Research Institute, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea.

出版信息

Biochim Biophys Acta. 2013 Dec;1832(12):1998-2008. doi: 10.1016/j.bbadis.2013.07.001. Epub 2013 Jul 10.

Abstract

Extracellular signal-regulated kinase (ERK) signals play important roles in cell death and survival. However, the role of ERK in the repair process after injury remains to be defined in the kidney. Here, we investigated the role of ERK in proliferation and differentiation of tubular epithelial cells, and proliferation of interstitial cells following ischemia/reperfusion (I/R) injury in the mouse kidney. Mice were subjected to 30min of renal ischemia. Some mice were administered with U0126, a specific upstream inhibitor of ERK, daily during the recovery phase, beginning at 1day after ischemia until sacrifice. I/R caused severe tubular cell damage and functional loss in the kidney. Nine days after ischemia, the kidney was restored functionally with a partial restoration of damaged tubules and expansion of fibrotic lesions. ERK was activated by I/R and the activated ERK was sustained for 9days. U0126 inhibited the proliferation, basolateral relocalization of Na,K-ATPase and lengthening of primary cilia in tubular epithelial cells, whereas it enhanced the proliferation of interstitial cells and accumulation of extracellular matrix. Furthermore, U0126 elevated the expression of cell cycle arrest-related proteins, p21 and phospholylated-chk2 in the post-ischemic kidney. U0126 mitigated the post-I/R increase of Sec10 which is a crucial component of exocyst complex and an important factor in ciliogenesis and tubulogenesis. U0126 also enhanced the expression of fibrosis-related proteins, TGF-β1 and phosphorylated NF-κB after ischemia. Our findings demonstrate that activation of ERK is required for both the restoration of damaged tubular epithelial cells and the inhibition of fibrosis progression following injury.

摘要

细胞外信号调节激酶(ERK)信号在细胞死亡和存活中发挥重要作用。然而,ERK在肾脏损伤后修复过程中的作用仍有待明确。在此,我们研究了ERK在小鼠肾脏缺血/再灌注(I/R)损伤后肾小管上皮细胞增殖和分化以及间质细胞增殖中的作用。小鼠经历30分钟的肾脏缺血。一些小鼠在恢复阶段每天给予U0126(一种ERK的特异性上游抑制剂),从缺血后第1天开始直至处死。I/R导致肾脏严重的肾小管细胞损伤和功能丧失。缺血9天后,肾脏功能恢复,受损肾小管部分修复,纤维化病变扩大。ERK被I/R激活,且激活的ERK持续9天。U0126抑制肾小管上皮细胞的增殖、钠钾ATP酶的基底外侧重新定位以及初级纤毛的延长,而增强间质细胞的增殖和细胞外基质的积累。此外,U0126提高了缺血后肾脏中细胞周期阻滞相关蛋白p21和磷酸化chk2的表达。U0126减轻了I/R后Sec10的增加,Sec10是外泌体复合物的关键成分,也是纤毛发生和肾小管发生的重要因素。U0126还增强了缺血后纤维化相关蛋白TGF-β1和磷酸化NF-κB的表达。我们的研究结果表明,ERK的激活对于受损肾小管上皮细胞的恢复以及损伤后纤维化进展的抑制都是必需的。

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