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Shved, Natallia; Warsow, Gregor; Eichinger, Felix; Hoogewijs, David; Brandt, Simone; Wild, Peter; Kretzler, Matthias; Cohen, Clemens D.; Lindenmeyer, Maja T. (2017): Transcriptome-based network analysis reveals renal cell type-specific dysregulation of hypoxia-associated transcripts. In: Scientific Reports, Vol. 7, 8576
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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 HIF1 alpha and/or HIF2 alpha 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.