scholarly journals A mathematical model of distal nephron acidification: diuretic effects

2008 ◽  
Vol 295 (5) ◽  
pp. F1353-F1364 ◽  
Author(s):  
Alan M. Weinstein
Keyword(s):  
Local Effect ◽  
Acid Excretion ◽  
Distal Nephron ◽  
Nacl Transport ◽  
Model Calculations ◽  
Urinary Acidification ◽  
Voltage Dependent ◽  
Luminal Flow ◽  
Renal Tubular ◽  
Nacl Cotransport

Through their action on the distal nephron (DN), diuretics may produce systemic acid-base disturbances: metabolic alkalosis with thiazides or loop diuretics and metabolic acidosis with amiloride. Enhanced acid excretion may be due to a local effect on the diuretic target cell (a shift of Na+ reabsorption from NaCl transport to Na+/H+ exchange), or an effect at a distance: namely, increases in luminal fluid flow or luminal Na+ concentration may enhance more distal proton secretion. Both local and distance effects are supported by micropuncture data. In the present work, mathematical models of the distal convoluted tubule (DCT)/connecting tubule (CNT) (Weinstein AM, Am J Physiol Renal Physiol 289: F721–F741, 2005), and cortical and medullary collecting ducts (CD) (Weinstein AM, Am J Physiol Renal Physiol 283: F1237–F1251, 2002) have been concatenated to yield a model of rat DN. Among the segments of this DN, the DCT-CNT is responsible for the major portion of distal acidification. Predictions from the model calculations include the following. 1) With increasing distal Na+ delivery, there is little change in net acid excretion, but a shift in acidification locus from shared DCT and CNT contributions, to DCT prominence. 2) Urinary acidification by thiazides is primarily local (in the DCT) via the shift in Na+ reabsorption from NaCl cotransport to entry via NHE2. Increased NaCl delivery to the CNT increases β-cell HCO3− secretion, and thus blunts urine acidification. 3) In contrast to conclusions drawn from the isolated CD model, inclusion of the CNT now reproduces the observed distal acidification defect found with ENaC block, so that this action of amiloride appears to be sufficient to produce “voltage-dependent” distal renal tubular acidosis. 4) The effect of furosemide to enhance distal urinary acidification is not reproduced by the model without major upregulation of CNT α-cell transport, perhaps as a result of increased luminal flow.

A mathematical model of rat collecting duct I. Flow effects on transport and urinary acidification

2002 ◽  
Vol 283 (6) ◽  
pp. F1237-F1251 ◽  
Author(s):  
Alan M. Weinstein
Keyword(s):  
Mathematical Model ◽  
Flow Rate ◽  
Collecting Duct ◽  
Osmotic Gradient ◽  
Acid Excretion ◽  
Urinary Ph ◽  
Model Calculations ◽  
Luminal Flow ◽  
High Flows ◽  
Net Acid Excretion

A mathematical model of the rat collecting duct (CD) has been developed by concatenating previously published models of cortical (Weinstein AM. Am J Physiol Renal Physiol 280: F1072–F1092, 2001); outer medullary (Weinstein AM. Am J Physiol Renal Physiol 279: F24–F45, 2000); and inner medullary segments (Weinstein AM. Am J Physiol Renal Physiol 274: F841–F855, 1998). Starting with end-distal tubular flow rate and composition, plus interstitial solute profiles, the model predicts urinary solute flows, including the buffer concentrations required to assess net acid excretion. In the model CD, the interstitial corticomedullary osmotic gradient provides the basis for the flow effect on the transport of several solutes. For substances that have an interstitial accumulation and that can have diffusive secretion (e.g., urea and NH[Formula: see text]), enhanced luminal flow increases excretion by decreasing luminal accumulation. For substances that are reabsorbed (e.g., K+ and HCO[Formula: see text]), and for which luminal accumulation can enhance reabsorption, increasing luminal flow again increases excretion by decreasing luminal solute concentration. In model calculations, flow-dependent increases in HCO[Formula: see text] and NH[Formula: see text] approximately balance, so net acid excretion is little changed by flow, albeit at a higher urinary pH. The model identifies delivery flow rate to the CD as a potent determinant of urinary pH, with high flows blunting maximal acidification. At even modestly high flows (9 nl · min−1 · tubule−1, with 6% of filtered Na+ entering the CD), the model cannot achieve a urinary pH <5.5 unless the delivered HCO[Formula: see text]concentration is extremely low (<2 mM). Nevertheless, simulation of Na2SO4 diuresis does yield both an increase in net acid excretion and a decrease in urinary HCO[Formula: see text](i.e., a decrease in pH) despite the increase in urinary flow. This model should provide a tool for examining hypotheses regarding transport defects underlying distal renal tubular acidosis.

Effect of parathyroid hormone on urinary acidification

1977 ◽  
Vol 232 (5) ◽  
pp. F429-F433 ◽  
Author(s):  
J. A. Arruda ◽  
L. Nascimento ◽  
C. Westenfelder ◽  
N. A. Kurtzman
Keyword(s):  
Parathyroid Hormone ◽  
Renal Tubular Acidosis ◽  
Ammonium Excretion ◽  
Distal Nephron ◽  
Urine Ph ◽  
Alkaline Urine ◽  
Acid Urine ◽  
Urinary Acidification ◽  
Before And After ◽  
Renal Tubular

The effect of parathyroid hormone (PTH) administration on urinary acidification was studied in intact and thyroparathyroidectomized dogs. PTH administration resulted in a significant increase in urine pH and HCO3 excretion. In dogs with maximally acid urine caused by Na2SO4 infusion PTH administration also led to a significant increase in urine pH and to a decrease in ammonium excretion. To examine the effect of PTH on H+ secretion in the distal nephron we measured the urine-blood (U-B) PCO2 gradient in dogs with maximally alkaline urine (urine pH greater than 7.8) before and after PTH administration. After infusion of the hormone, HCO3 excretion increased significantly but the U-B PCO2 gradient remained unchanged. The effects of PTH infusion on urinary acidification in animals with distal renal tubular acidosis caused by LiCl administration were also studied. PTH administration to these dogs increased HCO3 excretion to the same level seen in normal dogs. These data suggest that PTH does not inhibit distal H+ secretion but increases HCO3 excretion by depressing proximal HCO3 reabsorption.

scholarly journals Deficient acid handling with distal RTA in the NBCe2 knockout mouse

2015 ◽  
Vol 309 (6) ◽  
pp. F523-F530 ◽  
Author(s):  
Donghai Wen ◽  
Yang Yuan ◽  
Ryan J. Cornelius ◽  
Huaqing Li ◽  
Paige C. Warner ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Metabolic Acidosis ◽  
Knockout Mouse ◽  
Wild Type ◽  
Distal Nephron ◽  
Transepithelial Potential ◽  
Urinary Acidification ◽  
Renal Tubular ◽  
Acid Loading ◽  
Acid Challenge

In many circumstances, the pathogenesis of distal renal tubular acidosis (dRTA) is not understood. In the present study, we report that a mouse model lacking the electrogenic Na+-HCO3− cotransporter [NBCe2/Slc4a5; NBCe2 knockout (KO) mice] developed dRTA after an oral acid challenge. NBCe2 expression was identified in the connecting tubule (CNT) of wild-type mice, and its expression was significantly increased after acid loading. NBCe2 KO mice did not have dRTA when on a standard mouse diet. However, after acid loading, NBCe2 KO mice exhibited complete features of dRTA, characterized by insufficient urinary acidification, hyperchloremic hypokalemic metabolic acidosis, and hypercalciuria. Additional experiments showed that NBCe2 KO mice had decreased luminal transepithelial potential in the CNT, as revealed by micropuncture. Further immunofluorescence and Western blot experiments found that NBCe2 KO mice had increased expression of H+-ATPase B1 in the plasma membrane. These results showed that NBCe2 KO mice with acid loading developed increased urinary K+ and Ca2+ wasting due to decreased luminal transepithelial potential in the CNT. NBCe2 KO mice compensated to maintain systemic pH by increasing H+-ATPase in the plasma membrane. Therefore, defects in NBCe2 can cause dRTA, and NBCe2 has an important role to regulate urinary acidification and the transport of K+ and Ca2+ in the distal nephron.

scholarly journals Proximal and Distal Nephron-specific Adaptation to Furosemide

2021 ◽  
Author(s):  
Aram J. Krauson ◽  
Steven Schaffert ◽  
Elisabeth M. Walczak ◽  
Jonathan M. Nizar ◽  
Gwen M. Holdgate ◽  
...  
Keyword(s):  
Cell Number ◽  
Differentially Expressed ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
Distal Nephron ◽  
Transcriptional Responses ◽  
Cell Hyperplasia ◽  
Diuretic Resistance ◽  
Nephron Segments ◽  
Renal Tubular

ABSTRACTFurosemide, a widely prescribed diuretic for edema-forming states, inhibits sodium reabsorption in the thick ascending limb of the nephron. Tubular adaptation to diuretics has been observed, but the range of mechanisms along the nephron has not been fully explored. Using morphometry, we show that furosemide induces renal tubular epithelial hyperplasia selectively in distal nephron segments. By comparison, we find progressive cellular hypertrophy in proximal and distal nephron segments. We next utilize single cell RNA sequencing of vehicle- and furosemide-treated mice to define potential mechanisms of diuretic resistance. Consistent with distal tubular cell hyperplasia, we detect a net increase in DCT cell number and Birc5, an anti-apoptotic and pro-growth gene, in a subset of DCT cells, as the most prominently up-regulated gene across the nephron. We also map a gradient of cell-specific transcriptional changes congruent with enhanced distal sodium transport. Furosemide stimulates expression of the mitogen IGF-1. Thus, we developed a mouse model of inducible deletion of renal tubular IGF-1 receptor and show reduced kidney growth and proximal, but not distal, tubular hypertrophy by furosemide. Moreover, genes that promote enhanced bioavailability of IGF-1 including Igfbp1 and Igfbp5 are significantly and differentially expressed in proximal tubular segments and correspond to IGF-1R-dependent hypertrophy. In contrast, downstream PI3-kinase signaling genes including Pdk1, Akt1, Foxo3, FKBP4, Eif2BP4, and Spp1 are significantly and differentially expressed in distal nephron segments and correspond to IGF-1R-independent hypertrophy. These findings highlight novel mechanisms of tubular remodeling and diuretic resistance, provide a repository of transcriptional responses to a common drug, and expand the implications of long-term loop diuretic use for human disease.

Studies of the urinary acidification defect induced by lithium

1982 ◽  
Vol 242 (1) ◽  
pp. F23-F29 ◽  
Author(s):  
N. Bank ◽  
P. D. Lief ◽  
H. S. Aynedjian ◽  
B. F. Mutz
Keyword(s):  
Proximal Tubule ◽  
Renal Tubular Acidosis ◽  
Electrical Potential ◽  
Distal Renal Tubular Acidosis ◽  
Distal Nephron ◽  
Luminal Membrane ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
Convoluted Tubules

Experiments were carried out in rats and isolated turtle bladders to study the defect in H+ transport induced by LiCl. After 3-4 days of intraperitoneal LiCl, rats developed urinary findings of "distal" renal tubular acidosis. Proximal tubular fluid pH measured in situ by glass microelectrodes was higher in lithium-treated rats than in acidotic controls. Proximal fluid total CO2 [tCO2] was also higher, and the fraction of tCO2 leaving the proximal tubule was 14 vs. 7% (P less than 0.001). Impaired acidification was also apparent beyond distal convoluted tubules, as judged by normal distal tCO2 reabsorption but increased HCO3(-) in the urine. During NaHCO3 loading, the proximal defect was ameliorated but not the distal. Turtle bladder studies showed that mucosal lithium inhibits H+ secretion secondary to reducing transepithelial electrical potential, presumably by hyperpolarization of the luminal membrane. A similar mechanism may be responsible for lithium's effect on the distal nephron. Inhibition of proximal tubular HCO3(-) reabsorption is probably not attributable to electrical potential changes but might be due to interference of luminal membrane Na+ entry by Li+ and reduced (Na+ + Li+)-H+ exchange.

Passive NaCl transport in the flounder urinary bladder: predominance of a cellular pathway

1988 ◽  
Vol 255 (2) ◽  
pp. F229-F236 ◽  
Author(s):  
J. B. Stokes
Keyword(s):  
Urinary Bladder ◽  
High Resistance ◽  
Apical Membrane ◽  
Winter Flounder ◽  
Ionic Diffusion ◽  
Nacl Transport ◽  
Cellular Pathway ◽  
Ionic Conductances ◽  
Transepithelial Voltage ◽  
Nacl Cotransport

The urinary bladder of the winter flounder is a high-resistance epithelium that can absorb Na and Cl in an electrically silent manner. This active absorption (mucosa-to-serosa) of NaCl is, apparently uniquely, inhibited by mucosal hydrochlorothiazide (HCTZ). These experiments evaluated the notion that virtually all of the cellular Na and Cl permeation could be inhibited by mucosal HCTZ. Mucosal Ba2+ reduced the transepithelial conductance from 0.74 +/- 0.08 to 0.60 +/- 0.06 mS/cm2. Mucosal HCTZ reduced the serosa-to-mucosa flux (backflux) of Na from 0.70 +/- 0.08 to 0.29 +/- 0.03 mueq.cm-2.h-1 and the backflux of Cl from 1.92 +/- 0.22 to 0.38 +/- 0.03 mueq.cm-2.h-1. The treatment with these two agents caused the sum of the partial ionic conductances for Na and Cl to approximate the measured transepithelial conductance. In response to the imposition of a transepithelial voltage, the HCTZ-insensitive Na and Cl backfluxes behaved largely as predicted by the laws of simple ionic diffusion, although there was still a detectable cellular backflux. As judged from dilution voltages and tracer fluxes, the diffusional (paracellular) pathway(s) is nonselective for Na and Cl. The HCTZ-sensitive cellular Na and Cl backfluxes are dependent on the presence of mucosal Na and Cl. Neither backflux is significantly inhibited by serosal application of commonly used inhibitors of Na or Cl transport. The results demonstrate that the majority of passive Na and Cl flux is via a cellular pathway. The translocation across the apical membrane probably involves the same NaCl cotransport process responsible for NaCl absorption.

Decreased distal acidification in acute hypercapnia in the dog

1983 ◽  
Vol 244 (1) ◽  
pp. F19-F27
Author(s):  
H. J. Adrogue ◽  
B. J. Stinebaugh ◽  
A. Gougoux ◽  
G. Lemieux ◽  
P. Vinay ◽  
...  
Keyword(s):  
Extracellular Fluid ◽  
Respiratory Acidosis ◽  
Fractional Excretion ◽  
Distal Nephron ◽  
Sodium Potassium ◽  
Fractional Excretion Of Sodium ◽  
Dependent Component ◽  
Voltage Dependent ◽  
Bicarbonate Infusion

The present studies evaluate the effect of acute hypercapnia on distal nephron H+ secretion (DNH+S) in vivo by means of the urine-blood PCO2 difference (U-B PCO2) in alkaline urine. Bicarbonaturia was induced by either a sodium bicarbonate infusion or L-lysine administration. Our results demonstrate that the U-B PCO2, as a function of the urinary bicarbonate concentration, was significantly lower during acute respiratory acidosis; this effect was not dependent on changes in glomerular filtration rate and/or fractional excretion of sodium, potassium, and chloride. Infusion of the sodium salts of sulfate, a nonreabsorbable anion, did not correct the diminished U-B PCO2. Amiloride caused the U-B PCO2 to fall in normocapnic dogs but not in hypercapnic dogs. When hypercapnia was superimposed in dogs with extracellular fluid volume contraction, there were no changes in the U-B PCO2. This study indicates that acute hypercapnia in the intact dog decreases DNH+S and is compatible with an effect of hypercapnia on the voltage-dependent component of urine acidification. The mechanism appears to be direct rather than secondary to factors that influence the rate of sodium delivery to the distal nephron.

Effect of acute unilateral renal denervation on tubular sodium reabsorption in the dog

1977 ◽  
Vol 232 (1) ◽  
pp. F16-F19
Author(s):  
G. Nomura ◽  
T. Takabatake ◽  
S. Arai ◽  
D. Uno ◽  
M. Shimao ◽  
...  
Keyword(s):  
Renal Denervation ◽  
Renal Plasma Flow ◽  
Free Water ◽  
Sodium Reabsorption ◽  
Distal Nephron ◽  
Water Diuresis ◽  
Free Water Clearance ◽  
Water Excretion ◽  
Tubular Sodium Reabsorption ◽  
Renal Tubular

The effects of acute denervation of the kidney on renal tubular sodium and water excretion were studied in anesthetized, hypophysectomized, and cortisone-treated mongrel dogs during stable water diuresis produced by the infusion of 2.5% dextrose. In all experiments, denervation natriuresis, and diuresis were observed without significant change in glomerular filtration rate (GRF) and renal plasma flow (RPF). Fractional sodium delivery to the distal nephron (CNa + CH2O/100 ml GFR) and fractional free water clearance (CH23/100 ml GFR) was significantly greater in the denervated kidney compared with the innervated kidney (9.6+/-1.2 vs. 6.7+/-0.9% and 8.8+/-1.2 vs. 6.5+/-0.8%, respectively). Distal tubular sodium reabsorption (CH2O/(CNa + CH2O)) was not significantly different. We conclude that renal denervation primarily affects the proximal tubule as manifested by a decrease in the reabsorption of sodium and water. A small effect of denervation on the distal nephron is not completely ruled out.

A mathematical model of rat collecting duct III. Paradigms for distal acidification defects

2002 ◽  
Vol 283 (6) ◽  
pp. F1267-F1280 ◽  
Author(s):  
Alan M. Weinstein
Keyword(s):  
Collecting Duct ◽  
Critical Role ◽  
Electrical Potential ◽  
Electrical Potential Difference ◽  
Positive Finding ◽  
Model Calculations ◽  
Negative Finding ◽  
Transport Defect ◽  
Medullary Collecting Duct ◽  
Renal Tubular

The present clinical taxonomy of distal renal tubular acidoses includes “gradient,” “secretory,” and “voltage” defects. These categories refer to presumed collecting duct defects in which the epithelium may be abnormally permeable and unable to sustain an ion gradient, in which luminal proton ATPases are defective, or in which electrogenic Na+ reabsorption is impaired and luminal electronegativity is reduced. Classification of affected individuals is based on urinary pH and ion concentrations during spontaneous acidosis and during SO[Formula: see text] infusion, as well as urinary Pco 2 during HCO[Formula: see text] loading. A model of rat CD has been developed that has been used to examine determinants of urinary acidification (Weinstein AM. Am J Physiol Renal Physiol 283: F1252–F1266, 2002) and the interplay of HCO[Formula: see text] and PO[Formula: see text] loads to generate a disequlibrium pH and equilibrium Pco 2. In this paper, pure forms of gradient, voltage, and secretory defects are simulated, with attention to variability in the locus of the defect in the cortical (CCD), outer medullary (OMCD), or inner medullary collecting duct (IMCD). The objective of these calculations is to discover whether the intuitive description of these defects is sustained quantitatively. The most important positive finding is that the locus of the transport defect along the CD plays a critical role in the apparent severity of the lesion, with more proximal defects being less severe and more easily correctable. In particular, model calculations suggest that for gradient or secretory defects to be clinically detectable they need to involve the OMCD and/or IMCD. Additionally, the calculations reveal a possible mechanism for CD K+ wasting, which does not involve failure of H+-K+-ATPase but derives from a paracellular anion leak and thereby a more electronegative lumen. The most important negative finding is the lack of support for the category of renal tubular acidosis associated with a voltage defect. Although CD lesions that present with both K+ and H+ secretory defects suggest mediation by transepithelial electrical potential difference (PD), both PD changes and proton pump PD sensitivity appear too small to account for the observed abnormalities.

NaCl transport stimulates prostaglandin release in cultured renal epithelial (MDCK) cells

1986 ◽  
Vol 250 (5) ◽  
pp. C676-C681 ◽  
Author(s):  
A. Kurtz ◽  
J. Pfeilschifter ◽  
C. D. Brown ◽  
C. Bauer
Keyword(s):  
High Resistance ◽  
Loop Diuretic ◽  
Mdck Cells ◽  
Nacl Transport ◽  
Renal Tubular Cells ◽  
Prostaglandin Release ◽  
Pge2 Release ◽  
Pg Release ◽  
Renal Tubular ◽  
Stimulation Of

Prostaglandins (PGs) can modulate a variety of renal functions, including Na+ and Cl- reabsorption. However, it is not known if a direct interdependence exists between PG synthesis and transport activity. The present study was done to find out whether or not the rate of NaCl transport has an influence on PG synthesis in renal tubular cells. For our studies we used cultures of so-called high-resistance MDCK cells, which were originally derived from canine kidney. This cell type has a loop diuretic- and ouabain-sensitive NaCl transport that can be enhanced by activation of the adenylate cyclase (AC). In MDCK cell cultures we found that each state of increased NaCl transport during stimulation of AC by either epinephrine (10(-6) M), isoprenaline (10(-5) M), or forskolin (10(-5) M) was accompanied by a twofold increase in PG release. During inhibition of NaCl transport by furosemide (10(-4) M) or ouabain (2 X 10(-4) M), stimulation of AC failed to increase PGE2 release, whereas basal PG production was not inhibited by either furosemide or ouabain. Furthermore, PG formation during activation of AC was dependent on the concentration of extracellular Na+, whereas PG formation in the absence of activators of AC was independent of extracellular Na+. These results suggest that increased NaCl transport stimulates PG formation in cultures of high-resistance MDCK cells.

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