Lipoxins Attenuate Renal Fibrosis by Inducing let-7c and Suppressing TGFβR1
Lipoxins Attenuate Renal Fibrosis by Inducing let-7c and Suppressing TGFβR1
复制标题
DOI：
10.1681/asn.2012060550
复制
发表时间：
2013-04-01
影响因子：
13.6
通讯作者：
Godson, Catherine
中科院分区：
文献类型：
--
作者：
Brennan, Eoin P.;Nolan, Karen A.;Godson, Catherine
脂氧素是内源性产生的脂质介质，可促进炎症消退，并可抑制纤维化，提示其可能在调节肾脏疾病中发挥作用。在这里，脂氧素A4（LXA（4））通过上调microRNA let-7 c的机制，减弱了TGF-β 1诱导的人近端肾小管上皮细胞（HK-2）中纤连蛋白、N-钙粘蛋白、血小板反应蛋白和notch配体jagged-1的表达。相反，TGF-β 1抑制let-7 c的表达。在用LXA预处理的细胞中（4），尽管随后用TGF-β 1刺激，let-7 c的上调仍持续存在。在肾纤维化的单侧输尿管梗阻模型中，给予LXA（4）类似物诱导let-7 c上调。生物信息学分析表明，let-7 c的靶点包括TGF-β 1信号通路的几个成员，包括1型TGF-β受体。与此相一致，LXA（4）诱导的let-7 c上调抑制了1型TGF-β受体的表达和对TGF-β 1的反应。let-7 c的过表达模拟了LXA（4）在肾上皮中的抗纤维化作用;相反，针对let-7 c的抗miR减弱了LXA 4的作用。最后，我们观察到，与对照组相比，几个let-7 c靶基因在纤维化的人肾活检组织中上调。总之，这些结果表明，LXA（4）介导的let-7 c上调抑制TGF-β 1诱导的纤维化，并且let-7 c靶点的表达在人肾纤维化中失调。J Am Soc Nephrol 24：627-637，2013. doi：10.1681/ASN. 2012060550
Lipoxins, which are endogenously produced lipid mediators, promote the resolution of inflammation, and may inhibit fibrosis, suggesting a possible role in modulating renal disease. Here, lipoxin A4 (LXA(4)) attenuated TGF-beta 1-induced expression of fibronectin, N-cadherin, thrombospondin, and the notch ligand jagged-1 in cultured human proximal tubular epithelial (HK-2) cells through a mechanism involving upregulation of the microRNA let-7c. Conversely, TGF-beta 1 suppressed expression of let-7c. In cells pretreated with LXA(4), upregulation of let-7c persisted despite subsequent stimulation with TGF-beta 1. In the unilateral ureteral obstruction model of renal fibrosis, let-7c upregulation was induced by administering an LXA(4) analog. Bioinformatic analysis suggested that targets of let-7c include several members of the TGF-beta 1 signaling pathway, including the TGF-beta receptor type 1. Consistent with this, LXA(4)-induced upregulation of let-7c inhibited both the expression of TG F-beta receptor type 1 and the response to TGF-beta 1. Overexpression of let-7c mimicked the antifibrotic effects of LXA(4) in renal epithelia; conversely, anti-miR directed against let-7c attenuated the effects of LXA4. Finally, we observed that several let-7c target genes were upregulated in fibrotic human renal biopsies compared with controls. In conclusion, these results suggest that LXA(4)-mediated upregulation of let-7c suppresses TGF-beta 1-induced fibrosis and that expression of let-7c targets is dysregulated in human renal fibrosis. J Am Soc Nephrol 24: 627-637, 2013. doi: 10.1681/ASN.2012060550