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Papers In Press, published online ahead of print March 18, 2004
Department of Medicine and Therapeutics, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 0000
Corresponding Author: dsadlier.genome{at}mater.ie
Transcriptome analysis using microarray technology represents a powerful unbiased approach for delineating pathogenic mechanisms in disease. Here molecular mechanisms of renal tubulointerstitial fibrosis (TIF) were probed by monitoring changes in the renal transcriptome in a glomerular disease-dependent model of TIF (adriamycin nephropathy) using Affymetrix (mu74av2) microarray coupled with sequential primary biological function-focussed and secondary “baited”-global cluster analysis of gene expression profiles. Primary cluster analysis focused on mRNAs encoding matrix proteins and modulators of matrix turnover as classified by Onto-Compare and Gene Ontology and identified both molecules and pathways already implicated in the pathogenesis of TIF (e.g. TGFß1-CTGF-Fibronectin-1 pathway) and novel TIF-associated genes (e.g. SPARC, Matrilin-2). Specific gene expression patterns identified by primary ECM-focused cluster analysis were then used as bioinformatic bait in secondary global clustering, with which to search the renal transcriptome for novel modulators of TIF. Among the genes clustering with ECM proteins in the latter analysis were endoglin, clusterin and gelsolin. In several notable cases (e.g. claudin-1 and meprin-1-beta) the pattern of gene expression identified in adriamycin nephropathy in vivo was replicated during transdifferentiation of renal tubule epithelial cells to a fibroblast-like phenotype in vitro on exposure to TGF-beta and epidermal growth factor (EGF) suggesting a role in fibrogenesis. The further exploration of these complex gene networks should shed light on the core molecular pathways that underpin TIF in renal disease.
J. Biol. Chem, 10.1074/jbc.M313408200
Submitted on December 8, 2003
Revised on March 16, 2004
Accepted on March 18, 2004
Sequential extracellular matrix-focused and baited-global cluster analysis of serial transcriptomic profiles identifies candidate modulators of renal tubulointerstitial fibrosis in murine adriamycin induced nephropathy
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