The primary cilium as sensor of fluid flow: new building blocks to the model. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

Praetorius, Helle A.

doi:10.1152/ajpcell.00336.2014

Cited by 74 publications

(54 citation statements)

References 113 publications

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“…Although much remains to be understood about the mechanosensory ability of cells, primary cilium has been described as a major mechanosensory organelle (51)(52)(53). Given this notion, we postulated that primary cilium might have mediated the increase in transepithelial Ca 2+ transport that was observed after FSS exposure.…”

Section: Discussionmentioning

confidence: 94%

Fluid shear stress increases transepithelial transport of Ca ²⁺ in ciliated distal convoluted and connecting tubule cells

et al. 2017

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In kidney, transcellular transport of Ca is mediated by transient receptor potential vanilloid 5 and Na-Ca exchanger 1 proteins in distal convoluted and connecting tubules (DCTs and CNTs, respectively). It is not yet understood how DCT/CNT cells can adapt to differences in tubular flow rate and, consequently, Ca load. This study aims to elucidate the molecular mechanisms by which DCT/CNT cells sense fluid dynamics to control transepithelial Ca reabsorption and whether their primary cilia play an active role in this process. Mouse primary DCT/CNT cultures were subjected to a physiologic fluid shear stress (FSS) of 0.12 dyn/cm Transient receptor potential vanilloid 5 and Na-Ca exchanger 1 mRNA levels were significantly increased upon FSS exposure compared with static controls. Functional studies with Ca demonstrated a significant stimulation of transepithelial Ca transport under FSS compared with static conditions. Primary cilia removal decreased Ca transport in both static and FSS conditions, a finding that correlated with decreased expression of genes involved in transepithelial Ca transport; however, FSS-induced stimulation of Ca transport was still observed. These results indicate that nephron DCT and CNT segments translate FSS into a physiologic response that implicates an increased Ca reabsorption. Moreover, primary cilia influence transepithelial Ca transport in DCTs/CNTs, yet this process is not distinctly coupled to FSS sensing by these organelles.-Mohammed, S. G., Arjona, F. J., Latta, F., Bindels, R. J. M., Roepman, R., Hoenderop, J. G. J. Fluid shear stress increases transepithelial transport of Ca in ciliated distal convoluted and connecting tubule cells.

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Section: Discussionmentioning

confidence: 94%

Fluid shear stress increases transepithelial transport of Ca ²⁺ in ciliated distal convoluted and connecting tubule cells

et al. 2017

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“…Bending of the primary cilium causes ciliary influx of Ca 2+ , followed by an increase in cytosolic Ca 2+ (DeCaen, Delling, Vien, & Clapham, ; Delling, DeCaen, Doerner, Febvay, & Clapham, ; Praetorius, Frokiaer, Nielsen, & Spring, ; Praetorius & Spring, ). It is likely that the increase in intraciliary Ca 2+ does not spread to the cytosol suggesting the requirement of additional steps for amplification of the Ca 2+ signal, although details are not entirely clear and under debate (Delling et al, , ; Praetorius, ). Other cilia‐dependent signaling cascades affected by fluid flow include the canonical Wnt‐signaling pathway, which is restrained by fluid‐flow induced ciliary signaling in favor of non‐canonical Wnt signaling (Simons et al, ).…”

Section: Introductionmentioning

confidence: 99%

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

Kunnen

Malas

Semeins

et al. 2017

Journal Cellular Physiology

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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.

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“…Fluid flow stimulation in vitro deflects primary cilia on osteocytes, which causes an immediate rise in cytosolic Ca 2+ . This initial rise in intracellular Ca 2+ is amplified by the release of ATP and the subsequent purinergic response through P2X and P2Y receptors . In bone, a variety of P2X and P2Y receptors have been identified .…”

Section: Discussionmentioning

confidence: 99%

High shear stress amplitude in combination with prolonged stimulus duration determine induction of osteoclast formation by hematopoietic progenitor cells

et al. 2020

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To date, it is unclear how fluid dynamics stimulate mechanosensory cells to induce an osteoprotective or osteodestructive response. We investigated how murine hematopoietic progenitor cells respond to 2 minutes of dynamic fluid flow stimulation with a precisely controlled sequence of fluid shear stresses. The response was quantified by measuring extracellular adenosine triphosphate (ATP), immunocytochemistry of Piezo1, and sarcoplasmic/endoplasmic Ca2+ reticulum ATPase 2 (SERCA2), and by the ability of soluble factors produced by mechanically stimulated cells to modulate osteoclast differentiation. We rejected our initial hypothesis that peak wall shear stress rate determines the response of hematopoietic progenitor cells to dynamic fluid shear stress, as it had only a minor correlation with the abovementioned parameters. Low stimulus amplitudes corresponded to activation of Piezo1, SERCA2, low concentrations of extracellular ATP, and inhibition of osteoclastogenesis and resorption area, while high amplitudes generally corresponded to osteodestructive responses. At a given amplitude (3 Pa) and waveform (square), the duration of individual stimuli (duty cycle) showed a strong correlation with the release of ATP and osteoclast number and resorption area. Collectively, our data suggest that hematopoietic progenitor cells respond in a viscoelastic manner to loading, since a combination of high shear stress amplitude and prolonged duty cycle is needed to trigger an osteodestructive response. Plain Language Summary In case of painful joints or missing teeth, the current intervention is to replace them with an implant to keep a high‐quality lifestyle. When exercising or chewing, the cells in the bone around the implant experience mechanical loading. This loading generally supports bone formation to strengthen the bone and prevent breaking, but can also stimulate bone loss when the mechanical loading becomes too high around orthopedic and dental implants. We still do not fully understand how cells in the bone can distinguish between mechanical loading that strengthens or weakens the bone. We cultured cells derived from the bone marrow in the laboratory to test whether the bone loss response depends on (i) how fast a mechanical load is applied (rate), (ii) how intense the mechanical load is (amplitude), or (iii) how long each individual loading stimulus is applied (duration). We mimicked mechanical loading as it occurs in the body, by applying very precisely controlled flow of fluid over the cells. We found that a mechanosensitive receptor Piezo1 was activated by a low amplitude stimulus, which usually strengthens the bone. The potential inhibitor of Piezo1, namely SERCA2, was only activated by a low amplitude stimulus. This happened regardless of the rate of application. At a constant high amplitude, a longer duration of the stimulus enhanced the bone‐weakening response. Based on these results we deduce that a high loading amplitude tends to be bone weakening, and the longer this high amplitude persists, the wor...

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The primary cilium as sensor of fluid flow: new building blocks to the model. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

Abstract: Praetorius HA. The primary cilium as sensor of fluid flow: new building blocks to the model.

Cited by 74 publications

References 113 publications

Fluid shear stress increases transepithelial transport of Ca ²⁺ in ciliated distal convoluted and connecting tubule cells

Fluid shear stress increases transepithelial transport of Ca ²⁺ in ciliated distal convoluted and connecting tubule cells

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

High shear stress amplitude in combination with prolonged stimulus duration determine induction of osteoclast formation by hematopoietic progenitor cells

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The primary cilium as sensor of fluid flow: new building blocks to the model. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

Abstract: Praetorius HA. The primary cilium as sensor of fluid flow: new building blocks to the model.

Cited by 74 publications

References 113 publications

Fluid shear stress increases transepithelial transport of Ca 2+ in ciliated distal convoluted and connecting tubule cells

Fluid shear stress increases transepithelial transport of Ca 2+ in ciliated distal convoluted and connecting tubule cells

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

High shear stress amplitude in combination with prolonged stimulus duration determine induction of osteoclast formation by hematopoietic progenitor cells

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Fluid shear stress increases transepithelial transport of Ca ²⁺ in ciliated distal convoluted and connecting tubule cells

Fluid shear stress increases transepithelial transport of Ca ²⁺ in ciliated distal convoluted and connecting tubule cells