Flow-dependent transport in a mathematical model of rat proximal tubule (original) (raw)
Related papers
Acta Physiologica, 2006
Aim: By mathematical modelling, we analyse conditions for near-isotonic and isotonic transport by mammalian kidney proximal tubule. Methods: The model comprises compliant lateral intercellular space (lis) and cells, and infinitely large luminal and peritubular compartments with diffusible species: Na + , K + , Cl ) and an intracellular non-diffusible anion. Unknown model variables are solute concentrations, electrical potentials, volumes and hydrostatic pressures in cell and lis, and transepithelial potential. We used data mainly from rat proximal tubule to model epithelial cells and interspace with luminal and peritubular baths of identical composition. Results: The model of the tubular epithelium with physiological water permeability and paracellular electrical resistance generates solute coupled water uptake with an approx. 3% hypertonic absorbate. This function remains unperturbed following 'blocking' of apical water channels and in 'aquaporin-null' simulation. Reduced rate of volume reabsorption in AQP(-/-) mice would also require decreased apical sodium permeability. Paracellular convection accounts for approx. 36% of the net Na + absorption, and the model epithelium accomplishes uphill water transport similar to rat proximal tubule. Na + recirculation is required for truly isotonic transport. The tonicity of the absorbate and the recirculation flux depend critically on ion permeabilities of interspace basement membrane. Conclusion: Our model based on solute-solvent coupling in lateral space simulates major physiological features of proximal tubule, including significantly lower water permeability of the AQP1-null preparation, and a ratio of net sodium uptake and oxygen consumption exceeding that predicted from stoichiometry of the Na + /K + -pump. Physical properties of interspace basement membrane are critical for obtaining near-isotonic and truly isotonic transport. Keywords epithelial fluid transport, leaky epithelia, mammalian proximal tubule, mathematical model, Na + recirculation theory, solute coupled water transport.
A modeling study of solute reabsorption along rat proximal tubule
Acta Biotheoretica, 1993
We present a model of steady state solute and water reabsorption along the rat proximal tubule. Major co-and counter-transport systems in the apical and basolateral cell membranes are described using kinetic descriptions based on data from the flows and solute concentrations along the length of the proximal tubule as a function of filtration rate and peritubular solute concentrations. We show that for many aspects of proximal tubule transport physiology this kinetics-based model is an adequate representation of the mammalian proximal tubule.
Modeling Proximal Tubule Cell Homeostasis: Tracking Changes in Luminal Flow
Bulletin of Mathematical Biology, 2009
During normal kidney function, there are are routinely wide swings in proximal tubule fluid flow and proportional changes in Na + reabsorption across tubule epithelial cells. This "glomerulotubular balance" occurs in the absence of any substantial change in cell volume, and is thus a challenge to coordinate luminal membrane solute entry with peritubular membrane solute exit. In this work, linear optimal control theory is applied to generate a configuration of regulated transporters that could achieve this result. A previously developed model of rat proximal tubule epithelium is linearized about a physiologic reference condition; the approximate linear system is recast as a dynamical system; and a Riccati equation is solved to yield the optimal linear feedback that stabilizes Na + flux, cell volume, and cell pH. The first observation is that optimal feedback control is largely consigned to three physiologic variables, cell volume, cell electrical potential, and lateral intercellular hydrostatic pressure. Parameter modulation by cell volume stabilizes cell volume; parameter modulation by electrical potential or interspace pressure act to stabilize Na + flux and cell pH. This feedback control is utilized in a tracking problem, in which reabsorptive Na + flux varies over a factor of two. The resulting control parameters consist of two terms, an autonomous term and a feedback term, and both terms include transporters on both luminal and peritubular cell membranes. Overall, the increase in Na + flux is achieved with upregulation of luminal Na + /H + exchange and Na + -glucose cotransport, with increased peritubular and K + − Cl − cotransport, and with increased Na + , K + -ATPase activity. The configuration of activated transporters emerges as testable hypothesis of the molecular basis for glomerulotubular balance. It is suggested that the autonomous control component at each cell membrane could represent the cytoskeletal effects of luminal flow.
AJP: Renal Physiology, 2006
We have previously demonstrated that mouse proximal tubules in vitro respond to changes in luminal flow with proportional changes in Na+ absorption (Du Z, Duan Y, Yan Q, Weinstein AM, Weinbaum S, and Wang T. Proc Natl Acad Sci USA 101: 13068–13073, 2004). It was hypothesized that brush-border microvilli function as a sensor to detect and amplify luminal hydrodynamic forces and transmit them to the actin cytoskeleton. In the present study we examine whether 1) flow-dependent HCO3− transport is proportional to flow-dependent variations in microvillous torque (bending moment); 2) both luminal membrane Na+/H+ exchange (NHE3) and H+-ATPase activity are modulated by axial flow; and 3) paracellular permeabilities contribute to the flux perturbations. HCO3− absorption is examined by microperfusion of mouse S2 proximal tubules in vitro, with varying perfusion rates, and in the presence of the Na/H-exchange inhibitor EIPA, the H+-ATPase inhibitor bafilomycin, and the actin cytoskeleton inhibi...
Proceedings of the …, 2010
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.
Journal of Clinical Investigation, 1988
To examine the renal tubular sites and mechanisms involved in the effects of hypooncotic volume expansion (VE) on renal electrolyte excretion, we performed clearance and isolated tubular perfusion studies using intact and thyroparathyroidectomized (TPTX) rabbits. We also examined the effect of VE on luminal brush border transport. In the microperfusion studies, proximal convoluted (PCT) and straight (PST) tubules were taken from rabbits without prior VE or after 30 min of 6% (body wt) VE. Acute VE increased the percentage excretion of Na, Ca, and P in TPTX animals and the percentage and absolute excretions of these ions in intact rabbits. In PST from VE animals, fluid flux (Jv) was depressed compared with Jv in PST from nonVE rabbits: Jv = 0.18i0.03, (VE) vs. 0.31±0.03 nl/mm. min, (non VE) P < 0.02. Phosphate transport (Jp) in the PST from VE animals was also depressed: Jp = 1.58±0.10 (VE) vs. 2.62±0.47 pmol/mm. min, (nonVE) P < 0.05. Similar results were obtained with TPTX animals. In the PCT from VE animals, Jv was decreased (0.49±0.10 (VE) vs. 0.97±0.14 nl/mm * min, (non VE) P < 0.02), but Jp was not affected significantly. Transport inhibition was stable over-90 min of perfusion. In the brush border vesicle studies, sodium-dependent phosphate transport was inhibited compared with that in control animals, at the 9-, 30-, and 60-s time points. These findings indicate that the inhibition of renal ionic transport by VE occurs in both PCT and PST and is, in part, the result of a direct effect of VE on tubular transport mechanisms.
Understanding the Role of Paracellular Transport in the Proximal Tubule
News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society, 1998
Fluid and solute reabsorption by the proximal tubule is the result of both transcellular and paracellular flux. The role of transcellular transport has been extensively studied, but the importance of paracellular flux has not been as thoroughly investigated. The purpose of this review is to update concepts about the contribution of paracellular transport for reabsorption by the proximal tubule.
Transport characteristics of in vitro perfused proximal convoluted tubules
Kidney Int, 1982
Proximal convoluted tubules reabsorb the bulk of the sodium chloride and water present in the glomerular filtrate. In addition, the major portion of filtered bicarbonate, phosphate, glucose, and amino acids are reabsorbed in this nephron segment. All of this transport is accomplished isosmotically and without a measureable change in intraluminal sodium concentration. However, despite the absence of changes in luminal fluid osmolality and sodium concentration, important changes in luminal fluid constituents do occur. As will be discussed in this study and that of Barfuss and Schafer on the pars recta [1], these changes in luminal fluid constituents are felt to be an important determinant of transport events in late portions of the proximal convolution and in pars recta.
Clinical and Experimental Pharmacology and Physiology, 1987
In vivo micropuncture techniques, with and without peritubular capillary perfusion, were used to study the effects of high extracellular Na and C1 concentrations on transepithelial volume (J,) and sodium (JNa) fluxes in rat proximal tubules. 2. In a double blind manner, the shrinking drop technique of Gertz was used to measure J,; JN, was calculated from this and the tubular fluid Na concentration. 3. At both 184 and 279 mmol/l pericellular Na concentrations (both inside and outside the tubular epithelium), net J, decreased significantly by 15 and 64070, respectively. Net JNa remained constant at 184 but decreased by 29% at 279 mmol/l Na concentration. 4. Thus, at both Na concentrations, when translated to free flow conditions, fractional Na reabsorption must have decreased. These findings, also supported by previous results at these Na concentrations, indicate that active Na transport was inhibited by high pericellular Na concentrations. 5. When intratubular CI concentration was varied between 108 and 138 mmol/l while peritubular C1 was maintained constant (blood perfusing the capillaries), neither J, nor JNa changed. Thus, at zero tubular flow, differential CVHCO, concentrations do not provide significant driving forces for net J, or JNa. 6. When only intratubular but not peritubular Na was elevated to 279 mmol/l, J, and J,, increased markedly by 50 and 187070, providing evidence that a true solvent drag (solute drag) effect does exist in rat proximal tubules. 7. These findings offer a mechanism to explain why Na reabsorption is not increased when the filtered load of Na is increased with an elevation of plasma Na. That is, the high Na, which surrounds the tubular epithelium, inhibits Na and volume flux at the cellular level by mechanisms as yet unknown. The results also showed that differential CI/HCO, concentrations made no difference to Na or volume fluxes at zero tubular flow.