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
| Autor: | Yiping Wang, Hugh R. Brady, Lukas Kairaitis, Denise M. Sadlier, Sarah A. Roxburgh, Susan B. Connolly, David Harris, Niamh E. Kieran, Peter Doran, Derek P. Brazil |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Transcription Genetic Microarray Biology Biochemistry Transcriptome Mice Gene expression Animals Cluster Analysis Molecular Biology Cells Cultured Oligonucleotide Array Sequence Analysis Regulation of gene expression Extracellular Matrix Proteins Mice Inbred BALB C Antibiotics Antineoplastic Clusterin Gene Expression Profiling Epithelial Cells Cell Biology Fibrosis Molecular biology Extracellular Matrix Cell biology Gene expression profiling Disease Models Animal Kidney Tubules Gene Expression Regulation Doxorubicin Gene chip analysis biology.protein Kidney Diseases Transforming growth factor |
| Zdroj: | Journal of Biological Chemistry. 279:29670-29680 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m313408200 |
| Popis: | 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-focused 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. transforming growth factor beta1-CTGF-fibronectin-1 pathway) and novel TIF-associated genes (e.g. SPARC and Matrilin-2). Specific gene expression patterns identified by primary extracellular matrix-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-1beta) 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 transforming growth factor-beta and epidermal growth factor 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. |
| Databáze: | OpenAIRE |
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