Comprehensive transcriptome analysis of fluid shear stress altered gene expression in renal epithelial cells

S.J. Kunnen, T.B. Malas, C.M. Semeins, A.D. Bakker, D.J.M. Peters

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Renal epithelial cells are exposed to mechanical forces due to flow-induced shear stress within the nephrons. Shear stress is altered in renal diseases caused by tubular dilation, obstruction, and hyperfiltration, which occur to compensate for lost nephrons. Fundamental in regulation of shear stress are primary cilia and other mechano-sensors, and defects in cilia formation and function have profound effects on development and physiology of kidneys and other organs. We applied RNA sequencing to get a comprehensive overview of fluid-shear regulated genes and pathways in renal epithelial cells. Functional enrichment-analysis revealed TGF-β, MAPK, and Wnt signaling as core signaling pathways up-regulated by shear. Inhibitors of TGF-β and MAPK/ERK signaling modulate a wide range of mechanosensitive genes, identifying these pathways as master regulators of shear-induced gene expression. However, the main down-regulated pathway, that is, JAK/STAT, is independent of TGF-β and MAPK/ERK. Other up-regulated cytokine pathways include FGF, HB-EGF, PDGF, and CXC. Cellular responses to shear are modified at several levels, indicated by altered expression of genes involved in cell-matrix, cytoskeleton, and glycocalyx remodeling, as well as glycolysis and cholesterol metabolism. Cilia ablation abolished shear induced expression of a subset of genes, but genes involved in TGF-β, MAPK, and Wnt signaling were hardly affected, suggesting that other mechano-sensors play a prominent role in the shear stress response of renal epithelial cells. Modulations in signaling due to variations in fluid shear stress are relevant for renal physiology and pathology, as suggested by elevated gene expression at pathological levels of shear stress compared to physiological shear.
Original languageEnglish
Pages (from-to)3615-3628
JournalJournal of Cellular Physiology
Volume233
Issue number4
DOIs
Publication statusPublished - 2018

Funding

We thank Ron Wolterbeek (Medical Statistics, LUMC) for support with statistical analysis and Prof. Jenneke Klein-Nuland for facilitating the research with the parallel-plate fluid flow system. This work was supported by funding from the Netherlands Organization for Scientific Research (NWO) [grant number 820.02.016] and from the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program FP7/ 2077-2013 [REA grant agreement no. 317246]. We thank Ron Wolterbeek (Medical Statistics, LUMC) for support with statistical analysis and Prof. Jenneke Klein-Nuland for facilitating the research with the parallel-plate fluid flow system. This work was supported by funding from the Netherlands Organization for Scientific Research (NWO) [grant number 820.02.016] and from the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program FP7/2077-2013 [REA grant agreement no. 317246]. Netherlands Organization for Scientific Research (NWO), Grant number: 820.02.016; People Program (Marie Curie Actions) of the European Union's Seventh Framework Program FP7/2077-2013, Grant number: 317246

FundersFunder number
European Union's Seventh Framework Program FP7/2077
Netherlands Organization for Scientific Research
Seventh Framework Programme317246
FP7 People: Marie-Curie Actions
Marie Curie
Nederlandse Organisatie voor Wetenschappelijk Onderzoek820.02.016
Seventh Framework Programme

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