Next-generation sequencing identifies TGF-β1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy.
Next-generation sequencing identifies TGF-β1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy.
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DOI：
10.1016/j.bbadis.2012.01.008
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发表时间：
2012-04
影响因子：
6.2
通讯作者：
Martin, Finian
中科院分区：
文献类型：
--
作者：
Brennan, Eoin P.;Morine, Melissa J.;Walsh, David W.;Roxburgh, Sarah A.;Lindenmeyer, Maja T.;Brazil, Derek P.;Gaora, Peadar O.;Roche, Helen M.;Sadlier, Denise M.;Cohen, Clemens D.;Godson, Catherine;Martin, Finian
关键词：
转化生长因子-β（TGF-β1）与肾纤维化和糖尿病肾病（DN）的发生和进展有关，导致肾小管细胞上皮特征丧失。采用RNA-Seq技术对TGF-β1刺激的肾小管上皮细胞的转录谱进行了评估，鉴定了2027个差异表达基因。TGF-β1应答基因组中转录因子结合位点的启动子分析预测了多种转录网络的激活，包括NFκB。RNA-Seq与来自相同实验条件的微阵列数据的比较鉴定了RNA-Seq数据独有的低丰度转录物。我们通过分析DN患者与对照组肾活检的转录组数据，将这些发现与人类疾病进行比较，确定了179个受调控基因的共享子集。编码AMP相关激酶的ARK 5和编码TGF-β1的转化生长因子β诱导蛋白TGFBI在人DN中表达上调。ARK 5的抑制减弱了肾上皮对TGF-β1暴露的纤维化反应; TGFBI诱导的上皮细胞标记物-E-钙粘蛋白表达的沉默。我们在序列数据中鉴定了低丰度转录物，并验证了DN患者与活体供体肾小管富集肾活检中几种转录物（ANKRD 56，ENTPD 8）的表达水平。总之，我们已经确定了肾上皮细胞中TGF-β1驱动的促纤维化信号，这在DN肾转录组中也很明显。
Transforming growth factor-beta (TGF-β1) is implicated in the onset and progression of renal fibrosis and diabetic nephropathy (DN), leading to a loss of epithelial characteristics of tubular cells. The transcriptional profile of renal tubular epithelial cells stimulated with TGF-β1 was assessed using RNA-Seq, with 2027 differentially expressed genes identified. Promoter analysis of transcription factor binding sites in the TGF-β1 responsive gene set predicted activation of multiple transcriptional networks, including NFκB. Comparison of RNA-Seq with microarray data from identical experimental conditions identified low abundance transcripts exclusive to RNA-Seq data. We compared these findings to human disease by analyzing transcriptomic data from renal biopsies of patients with DN versus control groups, identifying a shared subset of 179 regulated genes. ARK5, encoding an AMP-related kinase, and TGFBI - encoding transforming growth factor, beta-induced protein were induced by TGF-β1 and also upregulated in human DN. Suppression of ARK5 attenuated fibrotic responses of renal epithelia to TGF-β1 exposure; and silencing of TGFBI induced expression of the epithelial cell marker – E-cadherin. We identified low abundance transcripts in sequence data and validated expression levels of several transcripts (ANKRD56, ENTPD8) in tubular enriched kidney biopsies of DN patients versus living donors. In conclusion, we have defined a TGF-β1-driven pro-fibrotic signal in renal epithelial cells that is also evident in the DN renal transcriptome.
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影响因子：
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