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.

doi:10.1038/s41598-017-08492-y

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Transcriptome-based network analysis reveals renal cell type-specific dysregulation of hypoxia-associated transcripts

Shved, Natallia Institute of Physiology and Division of Nephrology, University of Zurich, Switzerland
Warsow, Gregor Department of Anatomy and Cell Biology, Universitätsmedizin Greifswald, Germany - Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Eichinger, Felix Department of Medicine, University of Michigan, Ann Arbor, USA
Hoogewijs, David Department of Medicine/Physiology, University of Fribourg, Switzerland - Institute of Physiology and Division of Nephrology, University of Zurich, Switzerland
Brandt, Simone Institute of Pathology Molecular Pathology, University Hospital Zurich, Switzerland
Wild, Peter Institute of Pathology Molecular Pathology, University Hospital Zurich, Switzerland
Kretzler, Matthias Department of Medicine, University of Michigan, Ann Arbor, USA
Cohen, Clemens D. Institute of Physiology and Division of Nephrology, University of Zurich, Switzerland - Nephrological Center, Medical Clinic and Policlinic IV, University of Munich, Germany
Lindenmeyer, Maja T. Institute of Physiology and Division of Nephrology, University of Zurich, Switzerland - Nephrological Center, Medical Clinic and Policlinic IV, University of Munich, Germany

17.08.2017

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Scientific Reports. - 2017, vol. 7, no. 1, p. 8576

English 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.

Faculty

Faculté des sciences et de médecine

Department

Département de Médecine

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