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.
Highlights
Several organs are subject to variations in fluid flow rate in response to physiological stimuli, which could be detected by different cell types via mechano-sensing proteins or complexes
Since SMAD2/3 mediated gene transcription can be either restrained or induced by extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling, as shown before (Hough, Radu, & Dore, 2012; Kretzschmar, Doody, Timokhina, & Massague, 1999; Kunnen et al, 2017), we investigated the involvement of mitogen-activated protein kinase (MAPK)/ERK signaling in the shear stress response
In this study we used RNA sequencing to get a comprehensive overview of the transcriptome alterations upon fluid shear stress in proximal tubular epithelial cells
Summary
Several organs are subject to variations in fluid flow rate in response to physiological stimuli, which could be detected by different cell types via mechano-sensing proteins or complexes. Cilia-independent shear-induced alterations in renal signaling include increased Na+ and HCO3− reabsorption and autocrine TGF-β/ALK5 signaling (Kotsis, Boehlke, & Kuehn, 2013; Kunnen et al, 2017). It is currently not known in detail how fluid shear stress affects cellular behavior and which signaling pathways are altered. Cilia removal abrogated shear induced gene 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 an evident role in the shear stress response of renal epithelial cells. We showed that expression of several genes is elevated at pathological levels of shear stress compared to physiological controls, suggesting that variations in fluid shear stress might be relevant for the pathology in kidney diseases due to an imbalance in cellular signaling
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