Chloride transport in a mathematical model of the rat proximal tubule

1992 ◽  
Vol 263 (5) ◽  
pp. F784-F798 ◽  
Author(s):  
A. M. Weinstein
Keyword(s):  
Proximal Tubule ◽  
Chloride Transport ◽  
Basolateral Membrane ◽  
Model Calculations ◽  
Cl Transport ◽  
Luminal Membrane ◽  
Glomerular Filtrate ◽  
Thermodynamic Driving Force ◽  
Cytosolic Acidification ◽  
Rat Proximal Tubule

The proximal tubule model of this laboratory [Am. J. Physiol. 250 (Renal Fluid Electrolyte Physiol. 19): F860-F873, 1986] has been updated to examine proposed pathways for Cl- transport. Two additional buffer pairs have been added, i.e., HCO2-/H2CO2 and NH3/NH4+. At the luminal cell membrane Cl-/HCO2- and Cl-/HCO3- exchange are considered as pathways for Cl- entry, whereas at the peritubular membrane, Cl- exit occurs by either Na(+)-2HCO3-/Cl- exchange or K(+)-Cl- cotransport. Calculations with this model indicate that absolute proximal reabsorption of both Na+ and Cl- are critically dependent on the rate of luminal Na+/H+ exchange. In contrast, increases in the coefficient for Cl-/HCO2- exchange have little impact on overall Cl- flux, but, by enhancing base secretion, limit the depression of end-proximal HCO3-. Model calculations confirm those of Preisig and Alpern (J. Clin. Invest. 83: 1859–1867, 1989) showing that their measured value of luminal membrane H2CO2 permeability is inadequate to sustain the transcellular Cl- flux as Cl-/HCO2- exchange. Conversely, with sufficiently high H2CO2 permeability, luminal Cl- uptake is enhanced along the tubule, as HCO2- secretion and luminal acidification increase luminal H2CO2 to values severalfold greater than in glomerular filtrate. At the basolateral membrane, the thermodynamic driving force across the Na(+)-2HCO3-/Cl- exchanger is small. Although its contribution to steady-state Cl- exit may be less than the K(+)-Cl- cotransporter, the Na(+)-2HCO3-/Cl- exchanger can be a mechanism by which cytosolic acidification enhances peritubular Cl- transport, when luminal acidification enhances luminal Cl- uptake. A simulation is presented in which impermeant replacement of luminal Na+ leads to enhanced convective Cl- flux across the tight junction and alkalinization of the lateral interspace. In this setting, cytosolic Cl- depletion via the Na(+)-2HCO3-/Cl- exchanger may mimic luminal membrane Na(+)-Cl- cotransport.

Stimulation of chloride transport by cAMP in rat proximal tubules

1995 ◽  
Vol 268 (2) ◽  
pp. F204-F210 ◽  
Author(s):  
T. Wang ◽  
A. S. Segal ◽  
G. Giebisch ◽  
P. S. Aronson
Keyword(s):  
Proximal Tubule ◽  
Fluid Transport ◽  
Channel Blocker ◽  
Chloride Transport ◽  
Basolateral Membrane ◽  
Dibutyryl Camp ◽  
Cl Channel ◽  
Luminal Membrane ◽  
Cl Channels ◽  
Rat Proximal Tubule

We have previously demonstrated that formate and oxalate stimulate transcellular Cl- absorption (JCl) in the rat proximal tubule by a mechanism involving DIDS-sensitive anion exchange across the luminal membrane and diphenylamine-2-carboxylate (DPC)-sensitive Cl- channels in the basolateral membrane. Recent evidence indicates cAMP activation of Cl- channels in apical and basolateral membranes of proximal tubule cells. We therefore tested the effect of cAMP on Cl- and fluid transport in rat proximal tubule studied by luminal and capillary microperfusion in situ. The luminal perfusate contained 5 mM HCO3- and 145 mM Cl-, and the capillary perfusate contained 25 mM HCO3- and 110 mM Cl-, simulating conditions in the late proximal tubule. Addition of 0.5 mM dibutyryl cAMP markedly stimulated fluid absorption (Jv) and JCl. Similar effects resulted from addition of forskolin (10 microM) to stimulate cAMP production. The increments in Jv and JCl due to dibutyryl cAMP were abolished when the Cl- channel blocker DPC (200 microM) was added to the capillary perfusate but not when it was added to the lumen. The increments in Jv and JCl due to dibutyryl cAMP were unaffected by luminal DIDS (100 microM), which abolishes the increments in Jv and JCl induced by addition of oxalate. In contrast, the increments in Jv and JCl due to dibutyryl cAMP were abolished by luminal 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB; 10 microM), another Cl- channel blocker. Luminal NPPB had no effect on baseline Jv and JCl nor on the increments in Jv and JCl induced by addition of oxalate.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals A kinetically defined Na+/H+ antiporter within a mathematical model of the rat proximal tubule.

1995 ◽  
Vol 105 (5) ◽  
pp. 617-641 ◽  
Author(s):  
A M Weinstein
Keyword(s):  
Kinetic Model ◽  
Proximal Tubule ◽  
Membrane Vesicles ◽  
Model Calculations ◽  
Kinetic Formulation ◽  
Luminal Membrane ◽  
Least Squares Fit ◽  
Velocity Effect ◽  
Rat Proximal Tubule

The luminal membrane antiporter of the proximal tubule has been represented using the kinetic formulation of E. Heinz (1978. Mechanics and Engergetics of Biological Transport. Springer-Verlag, Berlin) with the assumption of equilibrium binding and 1:1 stoichiometry. Competitive binding and transport of NH+4 is included within this model. Ion affinities and permeation velocities were selected in a least-squares fit to the kinetic parameters determined experimentally in renal membrane vesicles (Aronson, P.S., M.A. Suhm, and J. Nee. 1983. Journal of Biological Chemistry. 258:6767-6771). The modifier role of internal H+ to enhance transport beyond the expected kinetics (Aronson, P.S., J. Nee, and M. A. Suhm. 1982. Nature. 299:161-163) is represented as a velocity effect of H+ binding to a single site. This kinetic formulation of the Na+/H+ antiporter was incorporated within a model of the rat proximal tubule (Weinstein, A. M. 1994. American Journal of Physiology. 267:F237-F248) as a replacement for the representation by linear nonequilibrium thermodynamics (NET). The membrane density of the antiporter was selected to yield agreement with the rate of tubular Na+ reabsorption. Simulation of 0.5 cm of tubule predicts that the activity of the Na+/H+ antiporter is the most important force for active secretion of ammonia. Model calculations of metabolic acid-base disturbances are performed and comparison is made among antiporter representations (kinetic model, kinetic model without internal modifier, and NET formulation). It is found that the ability to sharply turn off Na+/H+ exchange in cellular alkalosis substantially eliminates the cell volume increase associated with high HCO3- conditions. In the tubule model, diminished Na+/H+ exchange in alkalosis blunts the axial decrease in luminal HCO3- and thus diminishes paracellular reabsorption of Cl-. In this way, the kinetics of the Na+/H+ antiporter could act to enhance distal delivery of Na+, Cl-, and HCO3- in acute metabolic alkalosis.

scholarly journals Flow-dependent transport in a mathematical model of rat proximal tubule

2007 ◽  
Vol 292 (4) ◽  
pp. F1164-F1181 ◽  
Author(s):  
Alan M. Weinstein ◽  
Sheldon Weinbaum ◽  
Yi Duan ◽  
Zhaopeng Du ◽  
QingShang Yan ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Proximal Tubule ◽  
Low Flow ◽  
Diuretic Effect ◽  
Model Calculations ◽  
Enhanced Sensitivity ◽  
Luminal Membrane ◽  
Luminal Perfusion ◽  
Dependent Transport ◽  
Rat Proximal Tubule

The mathematical model of rat proximal tubule has been extended to include calculation of microvillous torque and to incorporate torque-dependent solute transport in a compliant tubule. The torque calculation follows that of Du Z, Yan Q, Duan Y, Weinbaum S, Weinstein AM, and Wang T ( Am J Physiol 290: F289–F296, 2006). In the model calculations, torque-dependent scaling of luminal membrane transporter density [either as an ensemble or just type 3 Na+/H+ exchanger (NHE3) alone] had a relatively small impact on overall Na+ reabsorption and could produce a lethal derangement of cell volume; coordinated regulation of luminal and peritubular transporters was required to represent the overall impact of luminal flow on Na+ reabsorption. When the magnitude of torque-dependent Na+ reabsorption in the model agrees with that observed in mouse proximal tubules, the model tubule shows nearly perfect perfusion-absorption balance at high luminal perfusion rates, but enhanced sensitivity of reabsorption at low flow. With a slightly lower coefficient for torque-sensitive transporter insertion, perfusion-absorption balance in the model tubule is closer to observations in the rat over a broader range of inlet flows. In simulation of hyperglycemia, torque-dependent transport attenuated the diuretic effect and brought the model tubule into closer agreement with experimental observation in the rat. The model was also extended to represent finite rates of hydration and dehydration of CO2 and H2CO3. With carbonic anhydrase inhibition, torque-dependent transport blunted the diuretic effect and enhanced the shift from paracellular to transcellular NaCl reabsorption. The new features of this model tubule are an important step toward simulation of glomerulotubular balance.

Urate transport in the proximal tubule: in vivo and vesicle studies

1985 ◽  
Vol 249 (6) ◽  
pp. F789-F798 ◽  
Author(s):  
A. M. Kahn ◽  
E. J. Weinman
Keyword(s):  
Proximal Tubule ◽  
Brush Border ◽  
Anion Exchanger ◽  
Basolateral Membrane ◽  
Membrane Vesicles ◽  
Transport Processes ◽  
Basolateral Membrane Vesicles ◽  
Urate Transport ◽  
Rat Proximal Tubule

The transport of urate in the mammalian nephron is largely confined to the proximal tubule. Depending on the species, net reabsorption or net secretion is observed. The rat, like the human and the mongrel dog, demonstrates net reabsorption of urate and has been the most extensively studied species. The unidirectional reabsorption and secretion of urate in the rat proximal tubule occur via a passive and presumably paracellular route and by a mediated transcellular route. The reabsorption of urate, and possibly its secretion, can occur against an electrochemical gradient. A variety of drugs and other compounds affect the reabsorption and secretion of urate. The effects of these agents depend on their site of application (luminal or blood), concentration, and occasionally their participation in transport processes that do not have affinity for urate. Recent studies with renal brush border and basolateral membrane vesicles from the rat and brush border vesicles from the dog have determined the mechanisms for urate transport across the luminal and antiluminal membranes of the proximal tubule cell. Brush border membrane vesicles contain an anion exchanger with affinity for urate, hydroxyl ion, bicarbonate, chloride, lactate, p-aminohippurate (PAH), and a variety of other organic anions. Basolateral membrane vesicles contain an anion exchanger with affinity for urate and chloride but not for PAH. Both membrane vesicle preparations also permit urate translocation by simple diffusion. A model for the transcellular reabsorption and secretion of urate in the rat proximal tubule is proposed. This model is based on the vesicle studies, and it can potentially explain the majority of urate transport data obtained with in vivo techniques.

Mechanisms of stimulation of proximal tubule chloride transport by formate and oxalate

1996 ◽  
Vol 271 (2) ◽  
pp. F446-F450 ◽  
Author(s):  
T. Wang ◽  
A. L. Egbert ◽  
T. Abbiati ◽  
P. S. Aronson ◽  
G. Giebisch
Keyword(s):  
Proximal Tubule ◽  
Chloride Transport ◽  
Rat Kidney ◽  
Exchange Process ◽  
Exchange Inhibitor ◽  
Volume Absorption ◽  
Peritubular Capillaries ◽  
Rat Proximal Tubule ◽  
Stimulation Of

We have previously demonstrated that formate and oxalate stimulate volume absorption in the rat proximal tubule, consistent with Cl-/formate and Cl-/oxalate exchange process across the apical membrane. To sustain Cl- absorption by these processes requires mechanisms for recycling formate and oxalate from lumen to cell. The aims of the present study were to characterize these mechanisms of formate and oxalate recycling. Proximal tubules and peritubular capillaries were simultaneously microperfused in the rat kidney in situ. Serum formate concentration was determined to be 56.5 +/- 7.7 microM. Addition of 5, 50, and 500 microM formate to both luminal and capillary perfusates significantly increased net Cl- absorption (Jcl) by 26, 26, and 46%, respectively. Jcl was stimulated 38% by 1 microM oxalate added to the perfusates. Removal of sulfate completely prevented the stimulation of Jcl by 1 microM oxalate but had no effect on the stimulation of Jcl by formate. Luminal addition of the Na+/H+ exchange inhibitor ethylisopropylamiloride completely blocked the stimulation of Jcl by 50 microM formate but had no effect on stimulation by oxalate. We conclude that physiological concentrations of formate and oxalate markedly stimulate Cl- and fluid absorption in the rat proximal convoluted tubule. Whereas formate recycling most likely involves Na+/H+ exchange in parallel with H(+)-coupled formate entry, oxalate recycling involves sodium-sulfate cotransport in parallel with sulfate/oxalate exchange.

Pathways for apical and basolateral membrane NH3 and NH4+ movement in rat proximal tubule

1990 ◽  
Vol 259 (4) ◽  
pp. F587-F593 ◽  
Author(s):  
P. A. Preisig ◽  
R. J. Alpern
Keyword(s):  
Proximal Tubule ◽  
Apical Membrane ◽  
Basolateral Membrane ◽  
Basolateral Membranes ◽  
Ammonia Addition ◽  
Rat Proximal Tubule

To examine the mechanism of preferential luminal ammonia secretion in the proximal tubule the apical and basolateral membrane pathways for NH3 and NH4+ movement were studied in the in vivo microperfused rat proximal tubule. Na and Cl were absent from all perfusates. Changes in pHi in response to rapid addition of NH3-NH4+ to either the luminal or peritubular perfusates were measured microfluorimetrically and expressed as the H(+)-equivalent flux (JeqH in pmol.mm-1.min-1). After ammonia addition ([NH3] 0.3 mM; [NH4+] 14.7 mM) to the luminal or peritubular fluids, pHi increased, and JeqH = 1,713 +/- 181 and 1,040 +/- 132 pmol.mm-1.min-1, respectively. To determine whether the above difference was due to NH3- or NH4(+)-driven fluxes, the effect of a fivefold greater [NH4+] ([NH3] 0.3 mM; [NH4+] 74.5 mM) on JeqH was examined. With luminal addition of a fivefold greater [NH4+], JeqH increased to 3,299 +/- 292 pmol.mm-1.min-1, demonstrating a pathway for NH4(+)-driven H+ efflux. One millimolar luminal amiloride inhibited JeqH in response to luminal NH3-NH4+ addition, suggesting that the amiloride-sensitive Na(+)-H+ antiporter mediates the NH4(+)-driven H+ efflux. JeqH was unaffected by addition of a fivefold greater [NH4+] to the peritubular perfusate, demonstrating the absence of an NH4(+)-driven H+ flux on the basolateral membrane. From these data, the calculated NH3 permeabilities were 6.2 +/- 1.3 and 7.0 +/- 0.9 X 10(-2) cm/s for the apical and basolateral membranes, respectively (NS). We conclude that apical and basolateral membrane NH3 permeabilities are similar and large. The apical membrane can also transport NH4+ on the amiloride-sensitive Na(+)-H+ antiporter.

Effect of norepinephrine on intracellular pH in kidney proximal tubule: role of Na+-( HCO 3 − ) n cotransport

1998 ◽  
Vol 275 (1) ◽  
pp. F33-F45 ◽  
Author(s):  
Solange Abdulnour-Nakhoul ◽  
Raja N. Khuri ◽  
Nazih L. Nakhoul
Keyword(s):  
Membrane Potential ◽  
Proximal Tubule ◽  
Intracellular Ph ◽  
Basolateral Membrane ◽  
Inhibitory Effect ◽  
Rate Of Change ◽  
Kidney Proximal Tubule ◽  
Luminal Membrane ◽  
Basolateral Membrane Potential

We examined the effect of norepinephrine (NE) on intracellular pH (pHi) and activity of Na+([Formula: see text]) in the isolated perfused kidney proximal tubule of Ambystoma, using single-barreled voltage and ion-selective microelectrodes. In control[Formula: see text] Ringer, addition of 10−6 M NE to the bath reversibly depolarized the basolateral membrane potential ( V 1), the luminal membrane potential ( V 2), and the transepithelial potential difference ( V 3) and increased pHi by 0.14 ± 0.02. These effects were mimicked by isoproterenol but were abolished after pretreatment with SITS or in the absence of CO2/[Formula: see text]. Removal of bath Na+ depolarized V 1 and V 2, hyperpolarized V 3, and decreased pHi. These effects are largely mediated by the electrogenic Na+-([Formula: see text]) n cotransporter. In the presence of NE, the effects of Na+ removal on membrane potential differences and the rate of change of pHi were significantly smaller. Reducing bath [Formula: see text] concentration from 10 to 2 mM at constant CO2 (pH 6.8) depolarized V 1 and V 2, decreased pHi, and lowered[Formula: see text]. These changes are also due to Na+-([Formula: see text]) n . In the presence of NE, reducing bath [[Formula: see text]] caused a smaller depolarizations of V 1 and V 2, and the rate of pHi decrease was significantly reduced. Our results indicate: 1) NE causes an increase in pHi; 2) the NE-induced alkalinization is mediated by a SITS-sensitive and[Formula: see text]-dependent transporter on the basolateral membrane; and 3) in the presence of NE, the reduced effects caused by basolateral[Formula: see text] changes or Na+ removal are indicative of an inhibitory effect of NE on Na+-([Formula: see text]) n cotransport.

scholarly journals Luminal and Basolateral Membrane Transport of Glutathione in Isolated Perfused S1, S2, and S3Segments of the Rabbit Proximal Tubule

2000 ◽  
Vol 11 (6) ◽  
pp. 1008-1015
Author(s):  
LISA D. PARKS ◽  
RUDOLFS K. ZALUPS ◽  
DELON W. BARFUSS
Keyword(s):  
Proximal Tubule ◽  
Membrane Transport ◽  
Basolateral Membrane ◽  
Bathing Solution ◽  
Disappearance Rate ◽  
Cellular Accumulation ◽  
Luminal Membrane ◽  
Perfusion Solution ◽  
Appearance Rate ◽  
Tubular Lumen

Abstract. Lumen-to-bath and bath-to-lumen transport rates of glutathione (GSH) were measured in isolated perfused S1, S2, and S3segments of the rabbit proximal tubule. In lumen-to-bath experiments, the perfusion solution contained 4.6 μM3H-GSH with or without 1.0 mM acivicin. In all three segments perfused without acivicin, luminal disappearance rate (JDL) and bath appearance rate (JAB) of3H-GSH were 14.5 ± 0.5 and 2.2 ± 0.8 fmol/min per mm tubule length, respectively. With acivicin present,JDLandJABwere reduced to 1.3 ± 0.4 and 0.5 ± 0.3, respectively, with no differences among segments. Cellular concentrations of3H-GSH in S1, S2, and S3segments when acivicin was absent were 23.1 ± 2.0, 31.7 ± 11.4, and 143.5 ± 17.9 μM, respectively. With acivicin in perfusate, cellular concentrations were reduced but there was no change in the heterogeneity profile. In bath-to-lumen transport experiments (S2segments only), the bathing solution contained 2.3 μM3H-GSH.3H-GSH appearance in the lumen (JAL, fmol/min per mm) and cellular accumulation from the bath were studied with and without acivicin in the perfusate.JALvalues were 3.0 ± 0.2 and 0.2 ± 0.03 while cellular concentrations were 9.5 ± 1.0 and 6.1 ± 0.5 μM, respectively. It is concluded that: (1) GSH is primarily removed from the luminal fluid after degradation to glycine, cysteine, and glutamate, which are absorbed; (2) GSH can be absorbed intact at the luminal membrane; (3) the S3segment has the greatest GSH cellular concentration because its basolateral membrane has less capacity for cell-to-bath transport of GSH; and (4) GSH can be secreted intact from the peritubular compartment into the tubular lumen.

scholarly journals SGLT2 Inhibitors: Physiology and Pharmacology

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0002772021
Author(s):  
Ernest M Wright
Keyword(s):  
Proximal Tubule ◽  
Glycosylated Hemoglobin ◽  
Blood Stream ◽  
Sglt2 Inhibitors ◽  
Luminal Membrane ◽  
Glucose Reabsorption ◽  
Lower Plasma Glucose ◽  
Glomerular Filtrate ◽  
Glucose Excretion

SGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 grams (one mole) of glucose from the glomerular filtrate each day. The natural glucoside phlorizin completely blocks glucose reabsorption. Oral SGLT2 inhibitors are rapidly absorbed into the blood stream where they remain in in the circulation for hours. On glomerular filtration, they bind specifically to SGLT2 in the luminal membrane of the early proximal tubule to reduce glucose reabsorption by 50-60%. Because of glucose excretion, these drugs lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. The drugs also protect against heart and renal failure. The aim of this review is to summarize what is currently known about the physiology of renal SGLTs and the pharmacology of SGLT drugs.

scholarly journals New insights into the cell biology of ischemic acute renal failure.

1991 ◽  
Vol 1 (12) ◽  
pp. 1263-1270 ◽  
Author(s):  
B A Molitoris
Keyword(s):  
Proximal Tubule ◽  
Cell Biology ◽  
Membrane Lipids ◽  
Basolateral Membrane ◽  
Surface Membrane ◽  
Membrane Lipid ◽  
Membrane Domains ◽  
Proximal Tubule Cells ◽  
Glomerular Filtrate ◽  
Tubule Cells

Proximal tubule cells play an essential role in the reabsorption of ions, water, and solutes from the glomerular filtrate. This is accomplished, in large part, by having a surface membrane polarized into structurally, biochemically, and physiologically distinct apical and basolateral membrane domains separated by cellular junctional complexes. Establishment and maintenance of these unique membrane domains are essential for the normal functioning of the cell. Ischemia results in the duration-dependent loss of apical and basolateral surface membrane lipid and protein polarity. Loss of surface membrane polarity is preceded by disruption of the microfilament network and opening of cellular tight junctions. Surface membrane lipids and proteins are then free to diffuse laterally within the bilayer into the alternate membrane domain. Functionally, ischemia-induced loss of epithelial polarity has been shown to be responsible for reduced sodium and glucose reabsorption. Reduced Na+ reabsorption has been related to redistribution of Na+, K(+)-ATPase into the apical membrane. During recovery from ischemic injury, proximal tubule cells undergo remodeling of the surface membrane such that the unique apical and basolateral membrane domains are reestablished, allowing for the return of normal cellular function.

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