Kruppel-Like Factor 15 Modulates Renal Interstitial Fibrosis by ERK/MAPK and JNK/MAPK Pathways Regulation
Kruppel-Like Factor 15 Modulates Renal Interstitial Fibrosis by ERK/MAPK and JNK/MAPK Pathways Regulation
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DOI：
10.1159/000355743
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发表时间：
2013-01-01
影响因子：
2.8
通讯作者：
Mei, Changlin
中科院分区：
文献类型：
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作者：
Gao, Xiang;Wu, Guiqun;Mei, Changlin
背景/目的：肾间质纤维化是进行性慢性肾脏病（CKD）的标志。既往研究报道kruppel样因子15（KLF 15）是心脏纤维化的重要调节因子，可降低系膜细胞细胞外基质的表达。然而，这种转录因子在肾间质纤维化中的作用还未见报道。方法：采用5/6肾切除大鼠模型，观察术后12周和24周残肾组织中KLF 15的表达。在体外实验中，我们检测了KLF 15表达改变对大鼠肾成纤维细胞（NRK-49 F）细胞外基质和促纤维化因子CTGF产生的影响，并进一步探讨了相关机制。结果如下：5/6肾切除大鼠肾组织中KLF 15水平显著降低，尤其是在24周时。我们的体外研究表明，KLF 15的过表达抑制了NRK-49 F细胞中基础和转化生长因子-β 1（TGF-β 1）诱导的细胞外基质和CTGF。此外，TGF-β 1介导的细胞外调节激酶（ERK）/丝裂原活化蛋白激酶（MAPK）和Jun N末端激酶（JNK）/ MAPK的激活可下调NRK-49 F细胞KLF 15的表达，增加细胞外基质和CTGF的水平，而ERK 1/2抑制剂和JNK抑制剂可完全消除这些作用。结论：提示KLF 15可能通过调节ERK/MAPK和JNK/MAPK信号通路在肾间质纤维化中发挥重要作用，并可能成为抗纤维化因子。版权所有（C）2013 S. Karger AG，巴塞尔
Background/Aims: Renal interstitial fibrosis is a hallmark of progressive chronic kidney disease (CKD). Previous studies reported that kruppel-like factor 15 (KLF15) is an important regulator of cardiac fibrosis and could reduce the expression of extracellular matrix in mesangial cells. However, the role of this transcription factor in renal interstitial fibrosis has not been reported. Methods: In this study, we examined KLF15 expression in the remnant kidney of 5/6 nephrectomized rats 12 or 24 weeks after operation. In vitro we examined the effect of altered KLF15 expression on the production of extracellular matrix and the pro-fibrotic factor CTGF in rat renal fibroblasts (NRK-49F), and further explored the related mechanisms. Results: The level of KLF15 was drastically decreased in the renal interstitium of 5/6 nephrectomized rats with progressive interstitial fibrosis, especially at 24 weeks. Our in vitro evidence showed that overexpression of KLF15 repressed basal and transforming growth factor-beta 1 ( TGF-beta 1)-induced extracellular matrix and CTGF in NRK-49F cells. In addition, TGF-beta 1-mediated activation of extracellular-regulated kinase (ERK) / mitogen-activated protein kinase (MAPK) and Jun N-terminal kinase (JNK) / MAPK downregulated KLF15 expression and increased the level of extracellular matrix and CTGF, and all these effects were completely abolished by ERK1/2 inhibitor and JNK inhibitor in NRK-49F cells. Conclusions: Our findings implicate that KLF15 plays an important role and may prove to be an antifibrotic factor in renal interstitial fibrosis through regulation of ERK/MAPK and JNK/MAPK signaling pathways. Copyright (C) 2013 S. Karger AG, Basel