脂氧素 A（4）抑制近端肾小管上皮细胞向间充质细胞的转化。

Lipoxin A(4) inhibits transition of epithelial to mesenchymal cells in proximal tubules.

机构信息

Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, China.

出版信息

Am J Nephrol. 2010;32(2):122-36. doi: 10.1159/000315121. Epub 2010 Jun 25.

DOI:10.1159/000315121

PMID:20714129

Abstract

BACKGROUND

Previous studies showed that connective tissue growth factor (CTGF)-induced proliferation of lung fibroblasts and production of chemokines in mesangial cells could be inhibited by lipoxin A(4) (LXA(4)). It is speculated that LXA(4) could modulate the CTGF-induced epithelial to mesenchymal transition.

METHODS

The expressions of alpha-smooth muscle actin (alpha-SMA), E-cadherin, integrin-linked kinase (ILK), extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K), Akt and Smad signaling were assessed by Western blot and/or real-time RT-PCR, and activation of Ras or ILK by activity assay, expressions of alpha-SMA and zonula occludens-1 by immunofluorescence assay in proximal tubular epithelial cells (HK-2).

RESULTS

Pretreatment of HK-2 cells with LXA(4) inhibited the morphological fibroblast-like changes and alpha-SMA expression induced by CTGF but not by transforming growth factor-beta(1) (TGF-beta(1)). The expressions of E-cadherin and zonula occludens-1 reduced by CTGF but not by TGF-beta(1) were increased by LXA(4). LXA(4) inhibited the expression and activity of ILK and activation of Ras, ERK1/2, PI3-K and Akt in HK-2 cells stimulated by CTGF. LXA(4) did not affect TGF-beta(1)-induced expression of ILK, Smad-2/3 phosphorylation and Smad-2's binding to Smad-4 and subsequent nuclear translocation.

CONCLUSION

LXA(4) inhibits the tubular epithelial to mesenchymal transition, initiated by CTGF but not by TGF-beta(1), via downregulation of ILK, Ras/MEK/ERK1/2 and PI3-K/Akt-dependent signal pathway stimulated by CTGF.

摘要

背景

先前的研究表明，脂氧素 A4（LXA4）可抑制结缔组织生长因子（CTGF）诱导的肺成纤维细胞增殖和系膜细胞中趋化因子的产生。推测 LXA4 可调节 CTGF 诱导的上皮-间充质转化。

方法

通过 Western blot 和/或实时 RT-PCR 评估α-平滑肌肌动蛋白（α-SMA）、E-钙黏蛋白、整合素连接激酶（ILK）、细胞外信号调节激酶 1/2（ERK1/2）、磷酸肌醇 3-激酶（PI3-K）、Akt 和 Smad 信号的表达，并通过活性测定评估 Ras 或 ILK 的激活，通过免疫荧光测定法评估近端肾小管上皮细胞（HK-2）中α-SMA 和封闭蛋白-1 的表达。

结果

LXA4 预处理可抑制 CTGF 诱导的 HK-2 细胞形态成纤维样改变和α-SMA 表达，但不能抑制转化生长因子-β1（TGF-β1）诱导的表达。CTGF 下调的 E-钙黏蛋白和封闭蛋白-1的表达增加，但 TGF-β1 诱导的表达不变。LXA4 抑制 CTGF 刺激的 HK-2 细胞中 ILK 的表达和活性以及 Ras、ERK1/2、PI3-K 和 Akt 的激活。LXA4 不影响 TGF-β1 诱导的 ILK 表达、Smad-2/3 磷酸化以及 Smad-2 与 Smad-4 的结合和随后的核转位。