Next-generation sequencing identifies TGF-尾1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy

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• 作者：Eoin P. Brennan^a ; ¹ ; Melissa J. Morine^b ; ^f ; ¹ ; David W. Walsh^a ; ¹ ; Sarah A. Roxburgh^a ; Maja T. Lindenmeyer^c ; Derek P. Brazil^d ; Peadar Ó ; . Gaora^e ; Helen M. Roche^b ; Denise M. Sadlier^a ; Clemens D. Cohen^c ; The GENIE Consortium² ; Catherine Godson^a ; ³ ; Finian Martin^a ; ³ ; ^{finian.martin@ucd.ie}
• 关键词：Diabetic nephropathy ; Renal tubule ; Epithelial&ndash ; mesenchymal transition ; Transforming growth-factor-beta1
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2012
• 期刊代码：19_09254439
• 类别：bio
• 出版时间：April, 2012
• 卷：1822
• 期：4
• 页码：589-599
• 文件大小：1490 K

摘要

Transforming growth factor-beta (TGF-尾1) 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-尾1 was assessed using RNA-Seq, with 2027 differentially expressed genes identified. Promoter analysis of transcription factor binding sites in the TGF-尾1 responsive gene set predicted activation of multiple transcriptional networks, including NF魏B. 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 鈥?encoding transforming growth factor, beta-induced protein were induced by TGF-尾1 and also upregulated in human DN. Suppression of ARK5 attenuated fibrotic responses of renal epithelia to TGF-尾1 exposure; and silencing of TGFBI induced expression of the epithelial cell marker 鈥?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-尾1-driven pro-fibrotic signal in renal epithelial cells that is also evident in the DN renal transcriptome.