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. / Shved, Natallia; Warsow, Gregor; Eichinger, Felix; Hoogewijs, David; Brandt, Simone; Wild, Peter; Kretzler, Matthias; Cohen, Clemens D; Lindenmeyer, Maja T.
In: SCI REP-UK, Vol. 7, No. 1, 17.08.2017, p. 8576.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Transcriptome-based network analysis reveals renal cell type-specific dysregulation of hypoxia-associated transcripts
AU - Shved, Natallia
AU - Warsow, Gregor
AU - Eichinger, Felix
AU - Hoogewijs, David
AU - Brandt, Simone
AU - Wild, Peter
AU - Kretzler, Matthias
AU - Cohen, Clemens D
AU - Lindenmeyer, Maja T
PY - 2017/8/17
Y1 - 2017/8/17
N2 - 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.
AB - 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.
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/s41598-017-08492-y
DO - 10.1038/s41598-017-08492-y
M3 - SCORING: Journal article
C2 - 28819298
VL - 7
SP - 8576
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
IS - 1
ER -