scholarly journals Solute transport and oxygen consumption along the nephrons: effects of Na+ transport inhibitors

2016 ◽  
Vol 311 (6) ◽  
pp. F1217-F1229 ◽  
Author(s):  
Anita T. Layton ◽  
Kamel Laghmani ◽  
Volker Vallon ◽  
Aurélie Edwards
Keyword(s):  
Oxygen Consumption ◽  
Rat Kidney ◽  
Substantial Reduction ◽  
Extracellular Fluid ◽  
Pressure Control ◽  
Transport Processes ◽  
Thick Ascending Limb ◽  
Transport Inhibitors ◽  
Solute Excretion ◽  
A Minor

Sodium and its associated anions are the major determinant of extracellular fluid volume, and the reabsorption of Na+ by the kidney plays a crucial role in long-term blood pressure control. The goal of this study was to investigate the extent to which inhibitors of transepithelial Na+ transport (TNa) along the nephron alter urinary solute excretion and TNa efficiency and how those effects may vary along different nephron segments. To accomplish that goal, we used the multinephron model developed in the companion study (28). That model represents detailed transcellular and paracellular transport processes along the nephrons of a rat kidney. We simulated the inhibition of the Na+/H+ exchanger (NHE3), the bumetanide-sensitive Na+-K+-2Cl− transporter (NKCC2), the Na+-Cl− cotransporter (NCC), and the amiloride-sensitive Na+ channel (ENaC). Under baseline conditions, NHE3, NKCC2, NCC, and ENaC reabsorb 36, 22, 4, and 7%, respectively, of filtered Na+. The model predicted that inhibition of NHE3 substantially reduced proximal tubule TNa and oxygen consumption (QO2). Whole-kidney TNa efficiency, as reflected by the number of moles of Na+ reabsorbed per moles of O2 consumed (denoted by the ratio TNa/QO2), decreased by ∼20% with 80% inhibition of NHE3. NKCC2 inhibition simulations predicted a substantial reduction in thick ascending limb TNa and QO2; however, the effect on whole-kidney TNa/QO2 was minor. Tubular K+ transport was also substantially impaired, resulting in elevated urinary K+ excretion. The most notable effect of NCC inhibition was to increase the excretion of Na+, K+, and Cl−; its impact on whole-kidney TNa and its efficiency was minor. Inhibition of ENaC was predicted to have opposite effects on the excretion of Na+ (increased) and K+ (decreased) and to have only a minor impact on whole-kidney TNa and TNa/QO2. Overall, model predictions agree well with measured changes in Na+ and K+ excretion in response to diuretics and Na+ transporter mutations.

scholarly journals A computational model for simulating solute transport and oxygen consumption along the nephrons

2016 ◽  
Vol 311 (6) ◽  
pp. F1378-F1390 ◽  
Author(s):  
Anita T. Layton ◽  
Volker Vallon ◽  
Aurélie Edwards
Keyword(s):  
Oxygen Consumption ◽  
Computational Model ◽  
Solute Transport ◽  
Rat Kidney ◽  
Transport Processes ◽  
Proximal Tubules ◽  
Thick Ascending Limb ◽  
Nephron Segments ◽  
Single Nephron ◽  
Luminal Flow

The goal of this study was to investigate water and solute transport, with a focus on sodium transport (TNa) and metabolism along individual nephron segments under differing physiological and pathophysiological conditions. To accomplish this goal, we developed a computational model of solute transport and oxygen consumption (QO2) along different nephron populations of a rat kidney. The model represents detailed epithelial and paracellular transport processes along both the superficial and juxtamedullary nephrons, with the loop of Henle of each model nephron extending to differing depths of the inner medulla. We used the model to assess how changes in TNa may alter QO2 in different nephron segments and how shifting the TNa sites alters overall kidney QO2. Under baseline conditions, the model predicted a whole kidney TNa/QO2, which denotes the number of moles of Na+ reabsorbed per moles of O2 consumed, of ∼15, with TNa efficiency predicted to be significantly greater in cortical nephron segments than in medullary segments. The TNa/QO2 ratio was generally similar among the superficial and juxtamedullary nephron segments, except for the proximal tubule, where TNa/QO2 was ∼20% higher in superficial nephrons, due to the larger luminal flow along the juxtamedullary proximal tubules and the resulting higher, flow-induced transcellular transport. Moreover, the model predicted that an increase in single-nephron glomerular filtration rate does not significantly affect TNa/QO2 in the proximal tubules but generally increases TNa/QO2 along downstream segments. The latter result can be attributed to the generally higher luminal [Na+], which raises paracellular TNa. Consequently, vulnerable medullary segments, such as the S3 segment and medullary thick ascending limb, may be relatively protected from flow-induced increases in QO2 under pathophysiological conditions.

scholarly journals Sex differences in solute transport along the nephrons: effects of Na+ transport inhibition

2020 ◽  
Vol 319 (3) ◽  
pp. F487-F505
Author(s):  
Rui Hu ◽  
Alicia A. McDonough ◽  
Anita T. Layton
Keyword(s):  
Transport Processes ◽  
Female Rats ◽  
Male Rats ◽  
Thick Ascending Limb ◽  
Female Rat ◽  
Male And Female ◽  
Notable Effect ◽  
Model Predictions ◽  
Solute Excretion ◽  
A Minor

Each day, ~1.7 kg of NaCl and 180 liters of water are reabsorbed by nephron segments in humans, with urinary excretion fine tuned to meet homeostatic requirements. These tasks are coordinated by a spectrum of renal Na+ transporters and channels. The goal of the present study was to investigate the extent to which inhibitors of transepithelial Na+ transport (TNa) along the nephron alter urinary solute excretion and how those effects may vary between male and female subjects. To accomplish that goal, we developed sex-specific multinephron models that represent detailed transcellular and paracellular transport processes along the nephrons of male and female rat kidneys. We simulated inhibition of Na+/H+ exchanger 3 (NHE3), bumetanide-sensitive Na+-K+-2Cl− cotransporter (NKCC2), Na+-Cl− cotransporter (NCC), and amiloride-sensitive epithelial Na+ channel (ENaC). NHE3 inhibition simulations predicted a substantially reduced proximal tubule TNa, and NKCC2 inhibition substantially reduced thick ascending limb TNa. Both gave rise to diuresis, natriuresis, and kaliuresis, with those effects stronger in female rats. While NCC inhibition was predicted to have only minor impact on renal TNa, it nonetheless had a notable effect of enhancing excretion of Na+, K+, and Cl−, particularly in female rats. Inhibition of ENaC was predicted to have opposite effects on the excretion of Na+ (increased) and K+ (decreased) and to have only a minor impact on whole kidney TNa. Unlike inhibition of other transporters, ENaC inhibition induced stronger natriuresis and diuresis in male rats than female rats. Overall, model predictions agreed well with measured changes in Na+ and K+ excretion in response to diuretics and Na+ transporter mutations.

Distribution and oligomeric association of splice forms of Na+-K+-ATPase regulatory γ-subunit in rat kidney

2002 ◽  
Vol 282 (3) ◽  
pp. F393-F407 ◽  
Author(s):  
Elena Arystarkhova ◽  
Randall K. Wetzel ◽  
Kathleen J. Sweadner
Keyword(s):  
Splice Variants ◽  
Rat Kidney ◽  
Thick Ascending Limb ◽  
Outer Medulla ◽  
Α Subunit ◽  
Proximal Tubule Cells ◽  
Γ Subunit ◽  
Outer Stripe ◽  
A Minor ◽  
Splice Forms

Renal Na+-K+-ATPase is associated with the γ-subunit (FXYD2), a single-span membrane protein that modifies ATPase properties. There are two splice variants with different amino termini, γa and γb. Both were found in the inner stripe of the outer medulla in the thick ascending limb. Coimmunoprecipitation with each other and the α-subunit indicated that they were associated in macromolecular complexes. Association was controlled by ligands that affect Na+-K+-ATPase conformation. In the cortex, the proportion of the γb-subunit was markedly lower, and the γa-subunit predominated in isolated proximal tubule cells. By immunofluorescence, the γb-subunit was detected in the superficial cortex only in the distal convoluted tubule and connecting tubule, which are rich in Na+-K+-ATPase but comprise a minor fraction of cortex mass. In the outer stripe of the outer medulla and for a short distance in the deep cortex, the thick ascending limb predominantly expressed the γb-subunit. Because different mechanisms maintain and regulate Na+ homeostasis in different nephron segments, the splice forms of the γ-subunit may have evolved to control the renal Na+ pump through pump properties, gene expression, or both.

Prostaglandin E2 inhibits oxygen consumption in rabbit medullary thick ascending limb

1990 ◽  
Vol 258 (5) ◽  
pp. F1372-F1378 ◽  
Author(s):  
S. Lear ◽  
P. Silva ◽  
V. E. Kelley ◽  
F. H. Epstein
Keyword(s):  
Oxygen Consumption ◽  
Collecting Duct ◽  
Renal Medulla ◽  
Cell Types ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Thick Ascending Limb ◽  
Medullary Thick Ascending Limb ◽  
Transport Inhibitors ◽  
Pg E2

The effect of prostaglandin (PG) E2 on transport-dependent oxygen consumption (QO2) of rabbit medullary thick ascending limb (MTAL) cells was studied. Exogenous PGE2, at a concentration of 30 microM, inhibited ouabain-sensitive QO2 by 70%. Addition of either ouabain or bumetanide, after PGE2, further depressed QO2, whereas PGE2 had no effect when added after these transport inhibitors. There was no significant inhibition of QO2 by PGE2 in the absence of either Na or Cl. The QO2 of amphotericin-treated cells was inhibited by the addition of PGE2. Therefore the inhibitory effect of PGE2 was on the transport-dependent moiety of QO2 and was independent of Na entry. Other prostanoids had no significant effect on MTAL QO2. Suspensions of isolated MTAL cells accumulated PGE2 at about one-fifth the rate of outer medullary collecting duct cells. Finally, PGE2 caused an increase in intracellular adenosine 3',5'-cyclic monophosphate levels by approximately 100%. Although the precise mechanism of action is unclear, PGE2, which is synthesized by several cell types in the renal medulla, exerts an inhibitory effect on transport in rabbit MTAL.

scholarly journals The sodium-activated sodium channel is expressed in the rat kidney thick ascending limb and collecting duct cells and is upregulated during high salt intake

2012 ◽  
Vol 303 (1) ◽  
pp. F105-F109 ◽  
Author(s):  
Lucienne S. Lara ◽  
Ryousuke Satou ◽  
Camille R. T. Bourgeois ◽  
Alexis A. Gonzalez ◽  
Andrea Zsombok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Salt Intake ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Extracellular Fluid ◽  
High Salt ◽  
Thick Ascending Limb ◽  
Principal Cells ◽  
High Salt Intake

Increased dietary salt triggers oxidative stress and kidney injury in salt-sensitive hypertension; however, the mechanism for sensing increased extracellular Na+ concentration ([Na+]) remains unclear. A Na+-activated Na+ channel (Na sensor) described in the brain operates as a sensor of extracellular fluid [Na+]; nonetheless, its presence in the kidney has not been established. In the present study, we demonstrated the gene expression of the Na sensor by RT-PCR and Western blotting in the Sprague-Dawley rat kidney. Using immunofluorescence, the Na sensor was localized to the luminal side in tubular epithelial cells of collecting ducts colocalizing with aquaporin-2, a marker of principal cells, and in thick ascending limb, colocalizing with the glycoprotein Tamm-Horsfall. To determine the effect of a high-salt diet (HSD) on Na sensor gene expression, we quantified its transcript and protein levels primarily in renal medullas from control rats and rats subjected to 8% NaCl for 7 days ( n = 5). HSD increased Na sensor expression levels (mRNA: from 1.2 ± 0.2 to 5.1 ± 1.3 au; protein: from 0.98 ± 0.15 to 1.74 ± 0.28 au P < 0.05) in the kidney medulla, but not in the cortex. These data indicate that rat kidney epithelial cells of the thick ascending limb and principal cells of the collecting duct possess a Na sensor that is upregulated by HSD, suggesting an important role in monitoring changes in tubular fluid [Na+].

Prostanoid signaling, localization, and expression of IP receptors in rat thick ascending limb cells

1998 ◽  
Vol 275 (6) ◽  
pp. F904-F914 ◽  
Author(s):  
Richard L. Hébert ◽  
Tim O’Connor ◽  
Chris Neville ◽  
Kevin D. Burns ◽  
Odette Laneuville ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Rat Kidney ◽  
Receptor Expression ◽  
Molecular Evidence ◽  
Thick Ascending Limb ◽  
Renal Epithelial Cells ◽  
Receptor Mrna ◽  
Ip Receptor ◽  
Receptor Cdna ◽  
Nucleotide Binding Proteins

It is widely held that only one prostacyclin (IP) receptor exists that can couple to guanine stimulatory nucleotide binding proteins (Gs) leading to activation of adenyl cyclase. Although IP receptor mRNA is expressed in vascular arterial smooth muscle cells and platelets, with lower level expression in mature thymocytes, splenic lymphocytes, and megakaryocytes, there is no molecular evidence for IP receptor expression in renal epithelial cells. The purpose of the present study was to obtain molecular evidence for the expression and localization of the IP receptor and to study the signaling pathways of IP receptor in rat medullary thick ascending limb (MTAL). Biochemical studies showed that IP prostanoids do not increase cAMP in rat MTAL. However, in the presence of vasopressin, inhibition of cAMP formation by prostacyclin (PGI2) analogs is pertussis toxin sensitive and does not activate protein kinase C. In situ hybridization studies localized IP receptor mRNA expression to MTAL in the rat kidney outer medulla. The results of RT-PCR of freshly isolated RNA from MTAL, with primers specific for the mouse IP receptor cDNA, produced an amplification product of the correct predicted size that contained an expected Nco I endonuclease restriction site. We conclude that rat renal epithelial cells express the IP receptor, coupled to inhibition of cAMP production.

Micropuncture analysis of single-nephron function in NHE3-deficient mice

1999 ◽  
Vol 277 (3) ◽  
pp. F447-F453 ◽  
Author(s):  
John N. Lorenz ◽  
Patrick J. Schultheis ◽  
Timothy Traynor ◽  
Gary E. Shull ◽  
Jürgen Schnermann
Keyword(s):  
Proximal Tubule ◽  
Filtration Rate ◽  
Distal Tubule ◽  
Transport Processes ◽  
Tubuloglomerular Feedback ◽  
Thick Ascending Limb ◽  
Fluid Reabsorption ◽  
Fluid Delivery ◽  
Single Nephron ◽  
Flow Pressure

The Na/H exchanger isoform 3 (NHE3) is expressed in the proximal tubule and thick ascending limb and contributes to the reabsorption of fluid and electrolytes in these segments. The contribution of NHE3 to fluid reabsorption was assessed by micropuncture in homozygous ( Nhe3 −/−) and heterozygous ( Nhe3 +/−) knockout mice, and in their wild-type (WT, Nhe3 +/+) littermates. Arterial pressure was lower in the Nhe3 −/−mice (89 ± 6 mmHg) compared with Nhe3 +/+ (118 ± 4) and Nhe3 +/−(108 ± 5). Collections from proximal and distal tubules demonstrated that proximal fluid reabsorption was blunted in both Nhe3 +/− and Nhe3 −/−mice (WT, 4.2 ± 0.3; Nhe3 +/−, 3.4 ± 0.2; and Nhe3 −/−, 2.6 ± 0.3 nl/min; P < 0.05). However, distal delivery of fluid was not different among the three groups of mice (WT, 3.3 ± 0.4 nl/min; Nhe3 +/−, 3.3 ± 0.2 nl/min; and Nhe3 −/−, 3.0 ± 0.4 nl/min; P < 0.05). In Nhe3 −/−mice, this compensation was largely attributable to decreased single-nephron glomerular filtration rate (SNGFR): 10.7 ± 0.9 nl/min in the Nhe3 +/+ vs. 6.6 ± 0.8 nl/min in the Nhe3 −/−, measured distally. Proximal-distal SNGFR differences in Nhe3 −/−mice indicated that much of the decrease in SNGFR was due to activation of tubuloglomerular feedback (TGF), and measurements of stop-flow pressure confirmed that TGF is intact in Nhe3 −/−animals. In contrast to Nhe3 −/−mice, normalization of early distal flow rate in Nhe3 +/−mice was not related to decreased SNGFR (9.9 ± 0.7 nl/min), but rather, to increased fluid reabsorption in the loop segment ( Nhe3 +/+, 2.6 ± 0.2; Nhe3 +/−, 3.6 ± 0.5 nl/min). We conclude that NHE3 is a major Na/H exchanger isoform mediating Na+ and fluid reabsorption in the proximal tubule. In animals with NHE3 deficiency, normalization of fluid delivery to the distal tubule is achieved through alterations in filtration rate and/or downstream transport processes.

Role of glucose in corneal metabolism

1985 ◽  
Vol 249 (5) ◽  
pp. C409-C416 ◽  
Author(s):  
R. S. Thies ◽  
L. J. Mandel
Keyword(s):  
Oxygen Consumption ◽  
Steady State ◽  
Specific Activity ◽  
Krebs Cycle ◽  
Lactate Production ◽  
Minor Component ◽  
Acid Oxidation ◽  
Endogenous Fatty Acid ◽  
Nonsteady State ◽  
A Minor

Glucose catabolism by glycolysis and the Krebs cycle was examined in the isolated rabbit cornea incubated with [6-14C]glucose. The production of [14C]lactate and 14CO2 from this substrate provided minimal values for the fluxes through these pathways since the tissue was in metabolic steady state but not isotopic steady state during the 40-min incubation. The specific activity of lactate under these conditions was one-third of that for [6-14C]glucose, and label dilution by exchange with unlabeled alanine was minimal, suggesting that glycogen degradation was primarily responsible for this dilution of label in the Embden-Meyerhof pathway. In addition, considerable label accumulation was found in glutamate and aspartate. Calculations revealed that these endogenous amino acid pools were not isotopically equilibrated after the incubation period, suggesting that they were responsible for the isotopic nonsteady state by exchange dilution through transaminase reactions with labeled intermediates. An estimate of glucose oxidation by the Krebs cycle, which was corrected for label dilution by exchange, indicated that glucose could account for most of the measured corneal oxygen consumption that was coupled to oxidative phosphorylation. A minor component of this respiration could not be accounted for by glucose or glycogen oxidation. Additional experiments suggested that endogenous fatty acid oxidation was probably also active under these conditions. Finally, reciprocal changes in plasma membrane Na+-K+-ATPase activity induced by ouabain and nystatin were found to concomitantly alter oxygen consumption rates and [14C]lactate production from [6-14C]glucose. These results demonstrated the capacity for regulating glycolysis and the Krebs cycle in response to changing energy demands in the cornea.

scholarly journals Extracellular Acid-Base Balance and Ion Transport Between Body Fluid Compartments

Physiology ◽  
2017 ◽  
Vol 32 (5) ◽  
pp. 367-379 ◽  
Author(s):  
Julian L. Seifter ◽  
Hsin-Yun Chang
Keyword(s):  
Ion Transport ◽  
Ph Regulation ◽  
Extracellular Fluid ◽  
Transport Processes ◽  
Electrolyte Balance ◽  
Ph Homeostasis ◽  
Acid Base Balance ◽  
Acid Base ◽  
Base Balance ◽  
Fluid Compartments

Clinical assessment of acid-base disorders depends on measurements made in the blood, part of the extracellular compartment. Yet much of the metabolic importance of these disorders concerns intracellular events. Intracellular and interstitial compartment acid-base balance is complex and heterogeneous. This review considers the determinants of the extracellular fluid pH related to the ion transport processes at the interface of cells and the interstitial fluid, and between epithelial cells lining the transcellular contents of the gastrointestinal and urinary tracts that open to the external environment. The generation of acid-base disorders and the associated disruption of electrolyte balance are considered in the context of these membrane transporters. This review suggests a process of internal and external balance for pH regulation, similar to that of potassium. The role of secretory gastrointestinal epithelia and renal epithelia with respect to normal pH homeostasis and clinical disorders are considered. Electroneutrality of electrolytes in the ECF is discussed in the context of reciprocal changes in Cl−or non Cl−anions and [Formula: see text].

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