Mechanical properties of primary cilia regulate the response to fluid flow

Rydholm, Susanna; Zwartz, Gordon J.; Kowalewski, Jacob M.; Kamali-Zare, Padideh; Frisk, Thomas; Brismar, Hjalmar

doi:10.1152/ajprenal.00657.2009

Cited by 100 publications

(96 citation statements)

References 35 publications

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“…For example, the calcium response triggered by flow in kidney cell cultures varies according to the flow regime and flow velocity in the system, suggesting that cilia can relay complex information about fluid forces to the cell (Rydholm et al, 2010). In endothelial cells, cilia can sense differential shear (Nauli et al, 2008), with increased shear (7.2 dynes/cm 2 ) inducing PKD1 proteolytic cleavage and abrogating ciliary mechanosensory potential without cilia shedding (Fig.…”

Section: Low-speed Flow Sensing Through Primary Ciliamentioning

confidence: 99%

Fluid flows and forces in development: functions, features and biophysical principles

et al. 2012

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Throughout morphogenesis, cells experience intracellular tensile and contractile forces on microscopic scales. Cells also experience extracellular forces, such as static forces mediated by the extracellular matrix and forces resulting from microscopic fluid flow. Although the biological ramifications of static forces have received much attention, little is known about the roles of fluid flows and forces during embryogenesis. Here, we focus on the microfluidic forces generated by cilia-driven fluid flow and heart-driven hemodynamics, as well as on the signaling pathways involved in flow sensing. We discuss recent studies that describe the functions and the biomechanical features of these fluid flows. These insights suggest that biological flow determines many aspects of cell behavior and identity through a specific set of physical stimuli and signaling pathways.

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Section: Low-speed Flow Sensing Through Primary Ciliamentioning

confidence: 99%

Fluid flows and forces in development: functions, features and biophysical principles

et al. 2012

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“…Both bending and pivoting could trigger membrane channels. Previous studies have used fluid flow to estimate primary cilium bending stiffness based on deformation profiles (11)(12)(13)(14), but the precise mechanical properties of the cilium remain unknown. It is likely that mechanosensation needs subtle coordination and calibration of the intracellular machinery involving adaptation and feedback mechanisms reacting to external stimuli, such as is the case in mammalian inner-ear cells, where active mechanical processes are crucial for hearing acuity (15,16).…”

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confidence: 99%

Intracellular and extracellular forces drive primary cilia movement

Battle

Ott

Burnette

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Primary cilia are ubiquitous, microtubule-based organelles that play diverse roles in sensory transduction in many eukaryotic cells. They interrogate the cellular environment through chemosensing, osmosensing, and mechanosensing using receptors and ion channels in the ciliary membrane. Little is known about the mechanical and structural properties of the cilium and how these properties contribute to ciliary perception. We probed the mechanical responses of primary cilia from kidney epithelial cells [Madin-Darby canine kidney-II (MDCK-II)], which sense fluid flow in renal ducts. We found that, on manipulation with an optical trap, cilia deflect by bending along their length and pivoting around an effective hinge located below the basal body. The calculated bending rigidity indicates weak microtubule doublet coupling. Primary cilia of MDCK cells lack interdoublet dynein motors. Nevertheless, we found that the organelles display active motility. 3D tracking showed correlated fluctuations of the cilium and basal body. These angular movements seemed random but were dependent on ATP and cytoplasmic myosin-II in the cell cortex. We conclude that force generation by the actin cytoskeleton surrounding the basal body results in active ciliary movement. We speculate that actin-driven ciliary movement might tune and calibrate ciliary sensory functions.

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“…In the collecting tubule, flow-stimulated K ϩ secretion is dependent on apical calcium entry; removal of Ca 2ϩ from the luminal perfusate prevents luminal Ca 2ϩ entry and abrogates flow stimulation of net K ϩ secretion (11). The entry of Ca 2ϩ is believed to be associated with large membrane strains in the vicinity of the basal body where the primary cilium can rotate near its insertion at the apical surface with little bending deformation along its axoneme (17). The bending moments on the primary cilia for a realistic flow profile are calculated in Liu et al (13), where the effects of circumferential stretch are separated from those of just flow without tubular diameter changes.…”

Section: Discussionmentioning

confidence: 99%

Regulation of glomerulotubular balance. III. Implication of cytosolic calcium in flow-dependent proximal tubule transport

Weinbaum

Weinstein

et al. 2015

American Journal of Physiology-Renal Physiology

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In the proximal tubule, axial flow (drag on brush-border microvilli) stimulates Na ϩ and HCO 3 Ϫ reabsorption by modulating both Na/H exchanger 3 (NHE3) and HATPase activity, a process critical to glomerulotubular balance. We have also demonstrated that blocking the angiotensin II receptor decreases baseline transport, but preserves the flow effect; dopamine leaves baseline fluxes intact, but abrogates the flow effect. In the current work, we provide evidence implicating cytosolic calcium in flow-dependent transport. Mouse proximal tubules were microperfused in vitro at perfusion rates of 5 and 20 nl/min, and reabsorption of fluid (Jv) and HCO 3 Ϫ (JHCO3) were measured. We examined the effect of high luminal Ca 2ϩ (5 mM), 0 mM Ca 2ϩ , the Ca 2ϩ chelator BAPTA-AM, the inositol 1,4,5-trisphosphate (IP3) receptor antagonist 2-aminoethoxydiphenyl borate (2-APB), and the Ca-ATPase inhibitor thapsigargin. In control tubules, increasing perfusion rate from 5 to 20 nl/min increased Jv by 62% and JHCO3 by 104%. With respect to Na ϩ reabsorption, high luminal Ca 2ϩ decreased transport at low flow, but preserved the flow-induced increase; low luminal Ca 2ϩ had little impact; both BAPTA and 2-APB had no effect on baseline flux, but abrogated the flow effect; thapsigargin decreased baseline flow, leaving the flow effect intact. With respect to HCO 3 Ϫ reabsorption, high luminal Ca 2ϩ decreased transport at low flow and mildly diminished the flow-induced increase; low luminal Ca 2ϩ had little impact; both BAPTA and 2-APB had no effect on baseline flux, but abrogated the flow effect. These data implicate IP3 receptor-mediated intracellular Ca 2ϩ signaling as a critical step in transduction of microvillous drag to modulate Na ϩ and HCO 3 Ϫ transport.calcium signals; tubule transport; flow-dependent; sodium bicarbonate; IP 3 receptor; extracellular Ca 2ϩ GLOMERULOTUBULAR BALANCE (GTB) was first established in the rat kidney via micropuncture (18), where variation in glomerular filtration (over a range of flows from 15 to 60 nl/min) was accompanied by a constant fractional proximal reabsorption. We have studied the mechanism of axial flow-induced changes in Na ϩ and HCO 3 Ϫ absorption by microperfusion of mouse proximal tubules in vitro under low and high flow rates. From these studies we have demonstrated that the underlying mechanism of GTB is the flow regulation of both Na/H exchanger 3 (NHE3) and H-ATPase activities. This modulation is torque dependent (bending moment at the apical membrane due to fluid flow) and requires the intact actin cytoskeleton (2). In the studies of mouse proximal tubule cells, we have shown that fluid shear stress stimulates NHE3 and H-ATPase trafficking to the apical and Na-K-ATPase to the basolateral membrane surfaces (6); this observation is supported by the mathematical model that shows both apical and basolateral transporters are regulated by flow (25). Regulatory mechanisms of the GTB, including the role of dopamine and ANG II receptors and the role of cAMP-PKA have been examined. From these st...

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Mechanical properties of primary cilia regulate the response to fluid flow

Cited by 100 publications

References 35 publications

Fluid flows and forces in development: functions, features and biophysical principles

Fluid flows and forces in development: functions, features and biophysical principles

Intracellular and extracellular forces drive primary cilia movement

Regulation of glomerulotubular balance. III. Implication of cytosolic calcium in flow-dependent proximal tubule transport

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