Mechanical strains induced by tubular flow affect the phenotype of proximal tubular cells

Essig, Marie; Terzi, Fabiola; Burtin, Martine; Friedlander, Gérard

doi:10.1152/ajprenal.2001.281.4.f751

Cited by 96 publications

(117 citation statements)

References 42 publications

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“…Under control conditions, ≈20% of the total NHE3 was located in the apical membrane (Table S1). Following exposure to 3-h FSS, concomitant with dramatic actin cytoskeleton reorganization (18,19), the overall expression of NHE3 was found to be significantly increased ( Fig. 1B and Table S1).…”

Section: Fss Increases Apical Nhe3 Abundance and Cytochalasin D Inhibmentioning

confidence: 95%

Shear stress-induced changes of membrane transporter localization and expression in mouse proximal tubule cells

Duan

Weinstein

Weinbaum

et al. 2010

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

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Our previous studies of microperfused single proximal tubule showed that flow-dependent Na + and HCO 3 − reabsorption is due to a modulation of both NHE3 and vacuolar H + -ATPase (V-ATPase) activity. An intact actin cytoskeleton was indicated to provide a structural framework for proximal tubule cells to transmit mechanical forces and subsequently modulate cellular functions. In this study, we have used mouse proximal tubule (MPT) cells as a model to study the role of fluid shear stress (FSS) on apical NHE3 and V-ATPase and basolateral Na/K-ATPase trafficking and expression. Our hypothesis is that FSS stimulates both apical and basolateral transporter expression and trafficking, which subsequently mediates salt and volume reabsorption. We exposed MPT cells to 0.2 dynes/cm 2 FSS for 3 h and performed confocal microscopy and Western blot analysis to compare the localization and expression of both apical and basolateral transporters in control cells and cells subjected to FSS. Our findings show that FSS leads to an increment in the amount of protein expression, and a translocation of apical NHE3 and V-ATPase from the intracellular compartment to the apical plasma membrane and Na/K-ATPase to the basolateral membrane. Disrupting actin by cytochalasin D blocks the FSS-induced changes in NHE3 and Na/K-ATPase, but not V-ATPase. In contrast, FSS-induced V-ATPase redistribution and expression are largely inhibited by colchicine, an agent that blocks microtubule polymerization. Our findings suggest that the actin cytoskeleton plays an important role in FSS-induced NHE3 and Na/K-ATPase trafficking, and an intact microtubule network is critical in FSS-induced modulation of V-ATPase in proximal tubule cells. , Cl − , and water reabsorption, as well as distal Na + absorption and K + secretion (1-5). In the kidney proximal tubule, glomerular tubular balance (GTB) allows for a rapid response to the changes of glomerular filtration rate (GFR) and provides for a nearly proportional change in Na + and HCO 3 − in the fluid filtered from the glomeruli (1). The physiological importance of this regulation is to prevent loss of solute following increases in GFR, and to preserve adequate distal delivery of sodium and fluid when GFR is reduced. This highly regulated uptake of Na + and HCO 3 − depends on the activity of a group of transport proteins that are located on the luminal and peritubular membrane of proximal tubule cells. Sodium reabsorption across the proximal tubule is driven by basolateral sodium pumps (Na/K-ATPase) and enters through apical NHE3. HCO 3 − reabsorption is regulated by apical transporters NHE3 and vacuolar H + -ATPase (V-ATPase) in tandem with the basolateral Na + /HCO 3 − cotransporter (NBC). We have previously investigated the role of FSS in modulating Na + and HCO 3 − reabsorption in mouse proximal tubule (MPT) using an in vitro microperfusion technique. Our findings indicated that both NHE3 (3, 6) and V-ATPase (3) activities were enhanced by increases in luminal flow rate. These experiments confirmed that bo...

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Section: Fss Increases Apical Nhe3 Abundance and Cytochalasin D Inhibmentioning

confidence: 95%

Shear stress-induced changes of membrane transporter localization and expression in mouse proximal tubule cells

Duan

Weinstein

Weinbaum

et al. 2010

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

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“…En revanche, en réponse au shear stress, ces fibres cytosoliques disparaissent et on observe un renforcement du réseau d'actine au pôle apical et en position latérale, associée à un assemblage des jonctions intercellulaires serrées et d'ancrage [11][12][13]. Cette réorganisation du cytosquelette d'actine joue un rôle important dans les effets du shear stress puisque sa perturbation par la cytochalasine D abolit l'activation des protéines de transport NHE3 et Na + /K + -ATPase induite par le FSS, et réduit la réabsorption de fluide induite par l'augmentation de la perfusion tubulaire [4,14,15].…”

Section: Réarrangement Du Cytosquelette Cellulaireunclassified

“…Compte tenu de ces mécanismes, on comprend assez aisément que la hauteur/ densité des microvillosités et la longueur du cil primaire jouent un rôle important dans la réponse cellulaire au shear stress. L'exposition des cellules tubulaires proximales à un FSS entraîne une inhibition des deux activateurs du plasminogène, tPA (tissue-type plasminogen activator) et uPA (urokinase) [12]. Dans la mesure où ces protéases sont capables de dégrader les protéines matricielles, cela suggère que le FSS pourrait favoriser l'accumulation de matrice extracellulaire -ou fibrose -observée dans la majorité des pathologies rénales.…”

Section: Quid De La Détection Du Cisaillement ?unclassified

“…Dans la mesure où ces protéases sont capables de dégrader les protéines matricielles, cela suggère que le FSS pourrait favoriser l'accumulation de matrice extracellulaire -ou fibrose -observée dans la majorité des pathologies rénales. C'est cette étude [12] qui a suggéré la première que le cisaillement urinaire jouerait potentiellement un rôle important dans la progression des néphropathies. FSS : fluid shear stress.…”

Section: Quid De La Détection Du Cisaillement ?unclassified

“…Son apparition dans l'espace interstitiel entre les tubules rénaux est fortement corrélée à la perte de la fonction rénale [25]. Il a été montré que le FSS réduit l'expression génique et protéique des activateurs du plasminogène uPA (urokinase) et tPa (tissue-type plasminogen activator) et inhibe leur activité [12] (Figure 2). Ces deux protéases participent directement ou indirectement à la dégradation des protéines matricielles.…”

Section: Des Protéines Impliquées Dans Les Néphropathies Sont Des Cibunclassified

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Human Kidney Proximal Tubule‐Microvascular Model Facilitates High‐Throughput Analyses of Structural and Functional Effects of Ischemia‐Reperfusion Injury

Shaughnessey,

Kann,

Charest

et al. 2023

Advanced Biology

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Kidney ischemia reperfusion injury (IRI) poses a major global healthcare burden, but effective treatments remain elusive. IRI involves a complex interplay of tissue‐level structural and functional changes caused by interruptions in blood and filtrate flow and reduced oxygenation. Existing in vitro models poorly replicate the in vivo injury environment and lack means of monitoring tissue function during the injury process. Here, a high‐throughput human primary kidney proximal tubule (PT)‐microvascular model is described, which facilitates in‐depth structural and rapid functional characterization of IRI‐induced changes in the tissue barrier. The PREDICT96 (P96) microfluidic platform's user‐controlled fluid flow can mimic the conditions of IR to induce pronounced changes in cell structure that resemble clinical and in vivo phenotypes. High‐throughput trans‐epi/endo‐thelial electrical resistance (TEER) sensing is applied to non‐invasively track functional changes in the PT‐microvascular barrier during the two‐stage injury process and over repeated episodes of injury. Notably, ischemia causes an initial increase in tissue TEER followed by a sudden increase in permeability upon reperfusion, and this biphasic response occurs only with the loss of both fluid flow and oxygenation. This study demonstrates the potential of the P96 kidney IRI model to enhance understanding of IRI and fuel therapeutic development.

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Mechanical strains induced by tubular flow affect the phenotype of proximal tubular cells

Cited by 96 publications

References 42 publications

Shear stress-induced changes of membrane transporter localization and expression in mouse proximal tubule cells

Shear stress-induced changes of membrane transporter localization and expression in mouse proximal tubule cells

Quand l’urine cisaille les cellules rénales

Human Kidney Proximal Tubule‐Microvascular Model Facilitates High‐Throughput Analyses of Structural and Functional Effects of Ischemia‐Reperfusion Injury

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