Cell Volume Regulation in the Proximal Tubule of Rat Kidney

Edwards, Aurélie

doi:10.1007/s11538-017-0338-6

Cited by 9 publications

(8 citation statements)

References 36 publications

(77 reference statements)

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“…Expression of Na + -K + -ATPase was raised concomitantly, albeit to a lesser extent (10%), so as to maintain intracellular [Na + ] below 25 mM. The basal expression of basolateral Na + -

cotransporters was also augmented (by 40%) to prevent large fluctuations in intracellular volume: adjustment of Na + -

cotransport is one of the mechanisms underlying cell volume regulation in the PT ( 16 , 59 , 61 ).…”

Section: Resultsmentioning

confidence: 99%

A model of calcium transport and regulation in the proximal tubule

Edwards

Bonny

2018

American Journal of Physiology-Renal Physiology

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The objective of this study was to examine theoretically how Ca2+ reabsorption in the proximal tubule (PT) is modulated by Na+ and water fluxes, parathyroid hormone (PTH), Na+-glucose cotransporter (SGLT2) inhibitors, and acetazolamide. We expanded a previously published mathematical model of water and solute transport in the rat PT (Layton AT, Vallon V, Edwards A. Am J Physiol Renal Physiol 308: F1343–F1357, 2015) that did not include Ca2+. Our results indicate that Ca2+ reabsorption in the PT is primarily driven by the transepithelial Ca2+ concentration gradient that stems from water reabsorption, which is itself coupled to Na+ reabsorption. Simulated variations in permeability or transporter activity elicit opposite changes in paracellular and transcellular Ca2+ fluxes, whereas a simulated decrease in filtration rate lowers both fluxes. The model predicts that PTH-mediated inhibition of the apical Na+/H+ exchanger NHE3 reduces Na+ and Ca2+ transport to a similar extent. It also suggests that acetazolamide- and SGLT2 inhibitor-induced calciuria at least partly stems from reduced Ca2+ reabsorption in the PT. In addition, backleak of phosphate (PO4) across tight junctions is predicted to reduce net PO4 reabsorption by ~20% under normal conditions. When transcellular PO4 transport is substantially reduced by PTH, paracellular PO4 flux is reversed and contributes significantly to PO4 reabsorption. Furthermore, PTH is predicted to exert an indirect impact on PO4 reabsorption via its inhibitory action on NHE3. This model thus provides greater insight into the mechanisms that modulate Ca2+ and PO4 reabsorption in the PT.

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“…Expression of Na + -K + -ATPase was raised concomitantly, albeit to a lesser extent (10%), so as to maintain intracellular [Na + ] below 25 mM. The basal expression of basolateral Na + -

cotransporters was also augmented (by 40%) to prevent large fluctuations in intracellular volume: adjustment of Na + -

cotransport is one of the mechanisms underlying cell volume regulation in the PT ( 16 , 59 , 61 ).…”

Section: Resultsmentioning

confidence: 99%

A model of calcium transport and regulation in the proximal tubule

Edwards

Bonny

2018

American Journal of Physiology-Renal Physiology

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“…The predicted NHE3 activity was then incorporated into a detailed mathematical model of the proximal convoluted tubule cell of a rat kidney (15,16,18). The model was formulated for the time-dependent state (7) , H 2 CO 2 , and glucose). The proximal tubule cell is represented as a well-stirred, compliant cellular compartment surrounded by luminal and peritubular (bath) solutions, the compositions of which are assumed known a priori (Table 1), as well as a lateral, paracellular space.…”

Section: Model Formulationmentioning

confidence: 99%

Predicted effect of circadian clock modulation of NHE3 of a proximal tubule cell on sodium transport

Wei

Gumz

2018

American Journal of Physiology-Renal Physiology

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Major renal functions such as renal blood flow, glomerular filtration rate, and urinary excretion are known to exhibit circadian oscillations. However, the underlying mechanisms that govern these variations have yet to be fully elucidated. To better understand the impact of the circadian clock on renal solute and water transport, we have developed a computational model of the renal circadian clock and coupled that model to an epithelial transport model of the proximal convoluted cell of the rat kidney. The activity of the Na-H exchanger 3 (NHE3) is assumed to be regulated by changes in transcription of the NHE3 mRNA due to regulation by circadian clock proteins. The model predicts the rhythmic oscillations in NHE3 activity, which gives rise to significant daily fluctuations in Na and water transport of the proximal tubule cell. Additionally, the model predicts that 1) mutation in period 2 (Per2) or cryptochrome 1 (Cry1) preserves the circadian rhythm and modestly raises Na reabsorption; 2) mutation in Bmal1 or CLOCK eliminates the circadian rhythm and modestly lowers Na reabsorption; 3) mutation in Rev-Erb or ROR-related orphan receptor (Ror) has minimal impact on the circadian oscillations. The model represents the first step in building a tool set aimed at increasing our understanding of how the molecular clock affects renal ion transport and renal function, which likely has important implications for kidney disease.

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“…The present nephron model predicts cellular solute concentrations, tubular flow, and luminal fluid solute concentrations. Except for the proximal tubule, nephron segments are represented as rigid tubules, and cell volume regulation [3] is not represented. Also, SNGFR is assumed known a priori .…”

Section: Discussionmentioning

confidence: 99%

“…To represent physiological processes and function changes of the kidney in diseases, one may employ a useful and non-invasive approach: computational modeling. Detailed models of solute and transport have been developed for renal epithelial cells [2, 3], tubular segments [4–6], and populations of nephrons [7, 8]. All these models, and other published ones, are formulated for the rat, due to the relatively plentiful anatomic, micropuncture, and electrophysiologic data available in rodents.…”

Section: Introductionmentioning

confidence: 99%

A computational model of epithelial solute and water transport along a human nephron

Layton

2019

PLoS Comput Biol

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We have developed the first computational model of solute and water transport from Bowman space to the papillary tip of the nephron of a human kidney. The nephron is represented as a tubule lined by a layer of epithelial cells, with apical and basolateral transporters that vary according to cell type. The model is formulated for steady state, and consists of a large system of coupled ordinary differential equations and algebraic equations. Model solution describes luminal fluid flow, hydrostatic pressure, luminal fluid solute concentrations, cytosolic solute concentrations, epithelial membrane potential, and transcellular and paracellular fluxes. We found that if we assume that the transporter density and permeabilities are taken to be the same between the human and rat nephrons (with the exception of a glucose transporter along the proximal tubule and the H + -pump along the collecting duct), the model yields segmental deliveries and urinary excretion of volume and key solutes that are consistent with human data. The model predicted that the human nephron exhibits glomerulotubular balance, such that proximal tubular Na + reabsorption varies proportionally to the single-nephron glomerular filtration rate. To simulate the action of a novel diabetic treatment, we inhibited the Na + -glucose cotransporter 2 (SGLT2) along the proximal convoluted tubule. Simulation results predicted that the segment’s Na + reabsorption decreased significantly, resulting in natriuresis and osmotic diuresis.

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Cell Volume Regulation in the Proximal Tubule of Rat Kidney

Cited by 9 publications

References 36 publications

A model of calcium transport and regulation in the proximal tubule

A model of calcium transport and regulation in the proximal tubule

Predicted effect of circadian clock modulation of NHE3 of a proximal tubule cell on sodium transport

A computational model of epithelial solute and water transport along a human nephron

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