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Transcriptome-based network analysis reveals renal cell type-specific dysregulation of hypoxia-associated transcripts
Natallia Shved1, Gregor Warsow2, Felix Eichinger3
1Institute of Physiology and Division of Nephrology, University of Zurich, Zurich, Switzerland.
Scientific Reports
|August 19, 2017
Summary
Hypoxia-induced factors (HIFs) and their target genes are dysregulated in chronic kidney disease (CKD). This study reveals compartment- and cell-specific transcriptional changes in kidney biopsies, impacting CKD progression.
Area of Science:
- Nephrology
- Molecular Biology
- Genomics
Background:
- Dysregulation of hypoxia-regulated transcriptional mechanisms is implicated in chronic kidney diseases (CKD).
- The precise contribution of hypoxia-induced factors (HIFs) and their downstream pathways to CKD pathogenesis remains incompletely understood.
- Understanding these mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of hypoxia-induced transcription factors (HIFs) and their target genes in the development and progression of CKD.
- To identify compartment- and cell type-specific transcriptional changes associated with HIF dysregulation in renal biopsies.
- To elucidate the relationship between HIF-target gene expression and kidney function decline.
Main Methods:
- Genome-wide expression profiling of over 200 renal biopsies across different CKD stages.
- Microarray analysis of proximal tubular cells and podocytes with suppressed HIF1α and/or HIF2α.
- Weighted Gene Co-expression Network Analysis (WGCNA) to identify coregulated gene modules.
- Gene expression analysis of hypoxia-interconnected pathways in relation to CKD severity.
Main Results:
- Significant positive and negative correlations between HIF-target genes and estimated glomerular filtration rate (eGFR) were observed in glomeruli and tubulointerstitium.
- Proximal tubular cells and podocytes exhibited cell type-specific dependencies on HIF1/HIF2, with pathway dysregulation upon suppression.
- WGCNA identified common and specific pathways, GO-terms, and transcription factors within gene modules.
- Hypoxia-interconnected pathways showed increased dysregulation with declining renal function in CKD patients.
Conclusions:
- The study demonstrates a compartment- and cell type-specific dysregulation of hypoxia-associated gene transcripts in CKD.
- These findings enhance the understanding of HIF dysregulation and transcriptional responses in the context of CKD.
- The results may inform future therapeutic strategies targeting hypoxia pathways in kidney disease.
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