Next-generation sequencing identifies TGF-β1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy

被引：66

作者：

Brennan, Eoin P. ^{[1
]}

Morine, Melissa J. ^{[2
,6
]}

Walsh, David W. ^{[1
]}

Roxburgh, Sarah A. ^{[1
]}

Lindenmeyer, Maja T. ^{[3
]}

Brazil, Derek P. ^{[4
]}

Gaora, Peadar O. ^{[5
]}

Roche, Helen M. ^{[2
]}

Sadlier, Denise M. ^{[1
]}

Cohen, Clemens D. ^{[3
]}

Godson, Catherine ^{[1
]}

Martin, Finian ^{[1
]}

机构：

[1] Univ Coll Dublin, UCD Conway Inst Biomol & Biomed Res, UCD Diabet Res Ctr, Dublin 4, Ireland

[2] Univ Coll Dublin, UCD Conway Inst Biomol & Biomed Res, Nutrigen Res Grp, Dublin 4, Ireland

[3] Univ Zurich Hosp, Div Nephrol, CH-8091 Zurich, Switzerland

[4] Queens Univ Belfast, Ctr Vis & Vasc Sci, Belfast, Antrim, North Ireland

[5] Univ Coll Dublin, UCD Conway Inst Biomol & Biomed Res, Sch Med & Med Sci, Dublin 4, Ireland

[6] Microsoft Res Univ Trento, Ctr Computat & Syst Biol COSBI, I-38068 Rovereto, Trento, Italy

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2012年 / 1822卷 / 04期

基金：

爱尔兰科学基金会;

关键词：

Diabetic nephropathy; Renal tubule; Epithelial-mesenchymal transition; Transforming growth-factor-beta1; TO-MESENCHYMAL TRANSITION; RNA-SEQ; ACTIVATION; INVASION; MODEL; SNAIL; ARK5; SLUG;

D O I：

10.1016/j.bbadis.2012.01.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Transforming growth factor-beta (TGF-beta 1) is implicated in the onset and progression of renal fibrosis and diabetic nephropathy (ON), leading to a loss of epithelial characteristics of tubular cells. The transcriptional profile of renal tubular epithelial cells stimulated with TGF-beta 1 was assessed using RNA-Seq, with 2027 differentially expressed genes identified. Promoter analysis of transcription factor binding sites in the TGF-beta 1 responsive gene set predicted activation of multiple transcriptional networks, including NF kappa 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 ON 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-beta 1 and also upregulated in human DN. Suppression of ARKS attenuated fibrotic responses of renal epithelia to TGF-beta 1 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-beta 1-driven pro-fibrotic signal in renal epithelial cells that is also evident in the DN renal transcriptome. (C) 2012 Elsevier B.V. All rights reserved.

引用

页码：589 / 599

页数：11

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