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Transcriptome-based network analysis reveals renal cell type-specific dysregulation of hypoxia-associated transcripts
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Transcriptome-based network analysis reveals renal cell type-specific dysregulation of hypoxia-associated transcripts
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Journal Article
Transcriptome-based network analysis reveals renal cell type-specific dysregulation of hypoxia-associated transcripts
2017
Overview
Accumulating evidence suggests that dysregulation of hypoxia-regulated transcriptional mechanisms is involved in development of chronic kidney diseases (CKD). However, it remains unclear how hypoxia-induced transcription factors (HIFs) and subsequent biological processes contribute to CKD development and progression. In our study, genome-wide expression profiles of more than 200 renal biopsies from patients with different CKD stages revealed significant correlation of HIF-target genes with eGFR in glomeruli and tubulointerstitium. These correlations were positive and negative and in part compartment-specific. Microarrays of proximal tubular cells and podocytes with stable HIF1α and/or HIF2α suppression displayed cell type-specific HIF1/HIF2-dependencies as well as dysregulation of several pathways. WGCNA analysis identified gene sets that were highly coregulated within modules. Characterization of the modules revealed common as well as cell group- and condition-specific pathways, GO-Terms and transcription factors. Gene expression analysis of the hypoxia-interconnected pathways in patients with different CKD stages revealed an increased dysregulation with loss of renal function. In conclusion, our data clearly point to a compartment- and cell type-specific dysregulation of hypoxia-associated gene transcripts and might help to improve the understanding of hypoxia, HIF dysregulation, and transcriptional program response in CKD.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/89
/ 38/39
/ 38/61
/ 38/77
/ 82/51
/ Basic Helix-Loop-Helix Transcription Factors - genetics
/ Basic Helix-Loop-Helix Transcription Factors - metabolism
/ Epidermal growth factor receptors
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Hypoxia
/ Hypoxia-Inducible Factor 1, alpha Subunit - genetics
/ Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
/ Kidney Glomerulus - metabolism
/ Kidney Glomerulus - pathology
/ Renal Insufficiency, Chronic - genetics
/ Renal Insufficiency, Chronic - pathology
/ Science
