Paracellular calcium transport across renal and intestinal epithelia

2014 ◽  
Vol 92 (6) ◽  
pp. 467-480 ◽  
Author(s):  
R. Todd Alexander ◽  
Juraj Rievaj ◽  
Henrik Dimke
Keyword(s):  
Thick Ascending Limb ◽  
Transport Pathway ◽  
Transport Pathways ◽  
Transcellular Transport ◽  
Renal Epithelium ◽  
Intestinal Epithelia ◽  
Physiological Processes ◽  
Renal Tubular Reabsorption ◽  
Renal Tubular ◽  
Paracellular Shunt

Calcium (Ca2+) is a key constituent in a myriad of physiological processes from intracellular signalling to the mineralization of bone. As a consequence, Ca2+ is maintained within narrow limits when circulating in plasma. This is accomplished via regulated interplay between intestinal absorption, renal tubular reabsorption, and exchange with bone. Many studies have focused on the highly regulated active transcellular transport pathways for Ca2+ from the duodenum of the intestine and the distal nephron of the kidney. However, comparatively little work has examined the molecular constituents creating the paracellular shunt across intestinal and renal epithelium, the transport pathway responsible for the majority of transepithelial Ca2+ flux. More specifically, passive paracellular Ca2+ absorption occurs across the majority of the intestine in addition to the renal proximal tubule and thick ascending limb of Henle’s loop. Importantly, recent studies demonstrated that Ca2+ transport through the paracellular shunt is significantly regulated. Therefore, we have summarized the evidence for different modes of paracellular Ca2+ flux across renal and intestinal epithelia and highlighted recent molecular insights into both the mechanism of secondarily active paracellular Ca2+ movement and the identity of claudins that permit the passage of Ca2+ through the tight junction of these epithelia.

An apical K+-dependent HCO3− transport pathway opposes transepithelial HCO3− absorption in rat medullary thick ascending limb

2004 ◽  
Vol 287 (1) ◽  
pp. F57-F63 ◽  
Author(s):  
Bruns A. Watts ◽  
David W. Good
Keyword(s):  
Initial Rate ◽  
Apical Membrane ◽  
Channel Blockers ◽  
Thick Ascending Limb ◽  
Acid Base ◽  
Transport Pathway ◽  
Transport Pathways ◽  
Medullary Thick Ascending Limb ◽  
And Function

Absorption of HCO3− in the medullary thick ascending limb (MTAL) is mediated by apical membrane Na+/H+ exchange. The identity and function of other apical acid-base transporters in this segment have not been defined. The present study was designed to examine apical membrane HCO3−/OH−/H+ transport pathways in the rat MTAL and to determine their role in transepithelial HCO3− absorption. MTALs were perfused in vitro in Na+- and Cl−-free solutions containing 25 mM HCO3−, 5% CO2. Lumen addition of either 120 mM Cl− or 50 mM Na+ (50 μM EIPA present) had no effect on intracellular pH (pHi). Lumen Cl− addition also had no effect on pHi in the presence of 145 mM Na+ or in the nominal absence of HCO3−/CO2. Thus there was no evidence for apical Cl−/HCO3− (OH−) exchange, Na+-dependent Cl−/HCO3− exchange, or Na+-HCO3− cotransport. In contrast, in tubules studied in Na+- and Cl−-free solutions containing 25 mM HCO3−, 5% CO2 and 120 mM K+, removal of luminal K+ induced a rapid and pronounced decrease in pHi (ΔpHi = 0.56 ± 0.06 pH U). pHi recovered following lumen K+ readdition. The initial rate of net base efflux induced by lumen K+ removal was decreased 85% at the same pHi in the nominal absence of HCO3−/CO2, indicating a dependence on HCO3−/CO2 and arguing against apical K+/H+ exchange. A combination of the apical K+ channel blockers quinidine (0.1 mM) and glybenclamide (0.25 mM) had no effect on the lumen K+-induced pHi changes, arguing against electrically coupled K+ and HCO3− conductances. The effect of lumen K+ on pHi was inhibited by 1 mM H2DIDS. In addition, lumen addition of DIDS increased transepithelial HCO3− absorption from 10.7 ± 0.7 to 14.9 ± 0.7 pmol·min−1·mm−1 ( P < 0.001) and increased pHi slightly in MTAL studied in physiological solutions (25 mM HCO3− and 4 mM K+). Lumen DIDS stimulated HCO3− absorption in the absence and presence of furosemide. These results are consistent with an apical membrane K+-dependent HCO3− transport pathway that mediates coupled transfer of K+ and HCO3− from cell to lumen in the MTAL. This mechanism, possibly an apical K+-HCO3− cotransporter, functions in parallel with apical Na+/H+ exchange and opposes transepithelial HCO3− absorption.

scholarly journals Cellular NH4+/K+ transport pathways in mouse medullary thick limb of Henle. Regulation by intracellular pH.

1992 ◽  
Vol 99 (3) ◽  
pp. 435-461 ◽  
Author(s):  
D Kikeri ◽  
A Sun ◽  
M L Zeidel ◽  
S C Hebert
Keyword(s):  
Intracellular Ph ◽  
Feedback Signal ◽  
Thick Ascending Limb ◽  
Transport Pathway ◽  
Cytosolic Ph ◽  
Transport Pathways ◽  
Buffering Power ◽  
Cd1 Mice ◽  
Apical Membranes ◽  
K Transport

Fluorescence and electrophysiological methods were used to determine the effects of intracellular pH (pHi) on cellular NH4+/K+ transport pathways in the renal medullary thick ascending limb of Henle (MTAL) from CD1 mice. Studies were performed in suspensions of MTAL tubules (S-MTAL) and in isolated, perfused MTAL segments (IP-MTAL). Steady-state pHi measured using 2,7-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF) averaged 7.42 +/- 0.02 (mean +/- SE) in S-MTAL and 7.26 +/- 0.04 in IP-MTAL. The intrinsic cellular buffering power of MTAL cells was 29.7 +/- 2.4 mM/pHi unit at pHi values between 7.0 and 7.6, but below a pHi of 7.0 the intrinsic buffering power increased linearly to approximately 50 mM/pHi unit at pHi 6.5. In IP-MTAL, NH4+ entered cells across apical membranes via both Ba(2+)-sensitive pathway and furosemide-sensitive Na+:K+(NH4+):2Cl- cotransport mechanisms. The K0.5 and maximal rate for combined apical entry were 0.5 mM and 83.3 mM/min, respectively. The apical Ba(2+)-sensitive cell conductance in IP-MTAL (Gc), which reflects the apical K+ conductance, was sensitive to pHi over a pHi range of 6.0-7.4 with an apparent K0.5 at pHi approximately 6.7. The rate of cellular NH4+ influx in IP-MTAL due to the apical Ba(2+)-sensitive NH4+ transport pathway was sensitive to reduction in cytosolic pH whether pHi was changed by acidifying the basolateral medium or by inhibition of the apical Na+:H+ exchanger with amiloride at a constant pHo of 7.4. The pHi sensitivities of Gc and apical, Ba(2+)-sensitive NH4+ influx in IP-MTAL were virtually identical. The pHi sensitivity of the Ba(2+)-sensitive NH4+ influx in S-MTAL when exposed to (apical+basolateral) NH4Cl was greater than that observed in IP-MTAL where NH4Cl was added only to apical membranes, suggesting an additional effect of intracellular NH4+/NH3 on NH4+ influx. NH4+ entry via apical Na+:K+ (NH4+):2Cl- cotransport in IP-MTAL was somewhat more sensitive to reductions in pHi than the Ba(2+)-sensitive NH4+ influx pathway; NH4+ entry decreased by 52.9 +/- 13.4% on reducing pHi from 7.31 +/- 0.17 to 6.82 +/- 0.14. These results suggest that pHi may provide a negative feedback signal for regulating the rate of apical NH4+ entry, and hence transcellular NH4+ transport, in the MTAL. A model incorporating these results is proposed which illustrates the role of both pHi and basolateral/intracellular NH4+/NH3 in regulating the rate of transcellular N H4+ transport in the MTAL.

IMMUNOREACTIVE GROWTH HORMONE IN PLASMA AND URINE IN JUVENILE DIABETICS BEFORE AND DURING INITIAL INSULIN TREATMENT

1974 ◽  
Vol 75 (1) ◽  
pp. 50-63 ◽  
Author(s):  
Kristian F. Hanssen
Keyword(s):  
Growth Hormone ◽  
Insulin Treatment ◽  
Juvenile Diabetes ◽  
Control Group ◽  
List Type ◽  
Newly Diagnosed ◽  
Renal Tubular Reabsorption ◽  
Juvenile Diabetics ◽  
The Mean ◽  
Renal Tubular

ABSTRACT Twenty newly diagnosed, but as yet untreated patients of both sexes with classical juvenile diabetes were investigated by determining the mean plasma immunoreactive growth hormone (IRHGH) and urinary IRHGH for a 24 hour period before and during initial insulin treatment. The plasma IRHGH was significantly higher (0.05 > P > 0.01) before than during initial insulin treatment. During initial insulin treatment, the mean plasma IRHGH was significantly higher (0.01 > P > 0.001) than in a control group. The urinary IRHGH was significantly higher (0.01 > P > 0.001) before than during insulin treatment. The increased urinary IRHGH observed before insulin treatment is thought to be partly due to a defective renal tubular reabsorption of growth hormone. No significant correlation was found between the mean blood sugar and plasma or urinary IRHGH either before or during insulin treatment.

Multihormonal regulation of nephron epithelia: achieved through combinational mode?

1995 ◽  
Vol 269 (4) ◽  
pp. R739-R748 ◽  
Author(s):  
C. De Rouffignac
Keyword(s):  
Sodium Chloride ◽  
Hormonal Regulation ◽  
Biological Effects ◽  
Basolateral Membrane ◽  
Positive Interactions ◽  
Thick Ascending Limb ◽  
Transport Pathways ◽  
Receptor Complexes ◽  
Nephron Segment ◽  
Urinary Concentrating Ability

The kidney is the main organ regulating composition of body fluids. A considerable number of hormones control the activity of renal cells to maintain hydromineral equilibrium. It becomes more and more difficult to interpret this multihormonal control in terms of regulatory processes. To illustrate this complexity, the hormonal regulation of electrolyte transport in the nephron thick ascending limb is taken as an example. This nephron segment is largely responsible for two kidney functions: the urinary-concentrating ability (by its capacity to deliver hypertonic sodium chloride into the medullary interstitium) and regulation of magnesium excretion into final urine. Six hormones are presently identified as acting on the transport of both sodium chloride and magnesium ions in this nephron segment. Therefore, the pertinent question is how the thick ascending limb and, hence, the kidney, is capable of regulating water balance independently from magnesium balance. It is proposed that the hormones act in combination: circulating levels of the individual hormones acting on these cells may determine the configuration of the paracellular and transcellular transport pathways of the epithelium either in the “sodium” or “magnesium” mode. The configuration would depend on the distribution and activity of the receptor at the surface of the basolateral membrane in contact with the circulating hormones. This distribution along with stimulation of respective signal transduction pathways would lead to the final biological effects. It is already known that the distribution of cell receptors may vary according to factors such as age, nutritional variability, hormonal status, degree of desensitization of the receptors, etc. The modulation of hormonal responses would depend therefore on the degree of coupling of hormone-receptor complexes to different intracellular transduction pathways and on the resulting negative and/or positive interactions between these pathways.

Sex differences in prenatal programming of hypertension by dexamethasone

2021 ◽  
pp. 153537022110032
Author(s):  
Issa Alhamoud ◽  
Susan K Legan ◽  
Jyothsna Gattineni ◽  
Michel Baum
Keyword(s):  
Blood Pressure ◽  
Plasma Renin ◽  
Female Offspring ◽  
Male Offspring ◽  
Thick Ascending Limb ◽  
Protein Abundance ◽  
Female Rat ◽  
Prenatal Programming ◽  
Transporter Protein ◽  
Renal Tubular

Prenatal dexamethasone has been shown to increase blood pressure in male offspring but the mechanism for the increase in blood pressure is unclear. The present study examined if prenatal programming by maternal injection of dexamethasone on days 15 and 16 of gestation affected the blood pressure comparably in female and male offspring. Our hypothesis was that males would be affected by prenatal dexamethasone to a greater extent than females and that either an increase in renal tubular transporter abundance or an increase in renin or aldosterone system would be associated with hypertension with prenatal programming. Prenatal dexamethasone increased blood pressure at two months and six months of age and resulted in proteinuria and albuminuria at six months in male but not female rat offspring. There was no effect of prenatal dexamethasone on blood pressure and proteinuria at one month in male and in female offspring. While prenatal dexamethasone increased male renal thick ascending limb sodium potassium two chloride cotransporter protein abundance at two months, prenatal dexamethasone on days 15 and 16 of gestation did not affect transporter abundance in males at other ages, nor did it affect proximal tubule sodium/hydrogen exchanger or distal convoluted tubule sodium chloride cotransporter protein abundance at any age. There was no difference in systemic renin or aldosterone in the prenatal dexamethasone group compared to same sex controls. In conclusion, male but not female offspring have an increase in blood pressure and urinary protein excretion with prenatal dexamethasone. The increase in blood pressure with prenatal programming was not associated with a consistent increase in renal tubular transporter protein abundance, nor plasma renin activity and serum aldosterone.

Dependency of Microdissected Nephron Segments upon Oxidative Phosphorylation and Exogenous Substrates: A Relationship between Tubular Anatomical Location in the Kidney and Metabolic Activity

1989 ◽  
Vol 77 (3) ◽  
pp. 287-295 ◽  
Author(s):  
Shozo Torikai
Keyword(s):  
Collecting Duct ◽  
Anatomical Location ◽  
Thick Ascending Limb ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Nephron Segments ◽  
Henle's Loop ◽  
Renal Tubular ◽  
Substrate Deprivation ◽  
Exogenous Substrates

1. In order to examine the possibility of heterogeneity in the dependence of renal tubular cells upon oxidative phosphorylation and exogenous substrates, the effects of antimycin A and substrate deprivation on adenosine 5′-triphosphate (ATP) content were examined in isolated rat nephron segments in vitro at 37°C. 2. Antimycin A (5 μmol/l) caused varying decrements in cell ATP level within 5 min in the following order: proximal tubules > cortical thick ascending limb of Henle's loop (cTAL) > cortical collecting duct (cCD) in the cortex, and thin descending limb of Henle's loop (TDL) > medullary thick ascending limb of Henle's loop (mTAL) > outer medullary collecting duct (omCD) in the inner stripe of the outer medulla. In the thick ascending limb and the collecting duct, the segments located in the cortex were more sensitive than those in the medulla. 3. Substrate deprivation for 30 min markedly decreased the cell ATP content in cortical and medullary proximal tubules and also in medullary TDL, whereas it caused only a slight decrease in cTAL and mTAL with no change in cCD and omCD. 4. Media made hypertonic by the addition of 200 mmol/l NaCl under aerobic conditions, increased the requirement for exogenous substrates in TDL and mTAL, but not in omCD. This stimulation was seen to a lesser extent in media made hypertonic by the addition of mannitol instead of NaCl. 5. Taking into consideration a knowledge of rat kidney architecture and intrarenal gradient of oxygen partial pressure, it is likely that the observed dependency upon both oxygen and exogenous substrates in the renal tubular cells reflects adaptation of such cells to their anatomical location, and to the availability of those substances in situ. Furthermore, extracellular sodium concentration and osmolarity stimulate metabolic requirements to a different extent among the nephron segments.

scholarly journals Early post-transplantation hypophosphatemia is associated with elevated FGF-23 levels

2011 ◽  
Vol 164 (5) ◽  
pp. 839-847 ◽  
Author(s):  
Andrea Trombetti ◽  
Laura Richert ◽  
Karine Hadaya ◽  
Jean-Daniel Graf ◽  
François R Herrmann ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Tubular Reabsorption ◽  
Phosphate Metabolism ◽  
Multivariate Models ◽  
Intact Pth ◽  
Post Transplantation ◽  
Estimated Gfr ◽  
Renal Tubular Reabsorption ◽  
Renal Tubular ◽  
Fgf 23

BackgroundWe examined the hypothesis that high FGF-23 levels early after transplantation contribute to the onset of hypophosphatemia, independently of parathyroid hormone (PTH) and other factors regulating phosphate metabolism.MethodsWe measured serum phosphate levels (sPi), renal tubular reabsorption of Pi (TmPi/GFR), estimated GFR (eGFR), intact PTH (iPTH), calcitriol, intact (int) and C-terminal (Cter) FGF-23, dietary Pi intake and cumulative doses of glucocorticoids in 69 patients 12 days (95% confidence interval, 10–13) after renal transplantation.ResultsHypophosphatemia was observed in 43 (62%) of the patients 12 days after transplantation. Compared with non-hypophosphatemic subjects, their post-transplantation levels of intact and CterFGF-23 were higher (195 (108–288) vs 48 (40–64) ng/l, P<0.002 for intFGF-23; 205 (116–384) vs 81 (55–124) U/ml, P<0.002, for CterFGF-23). In all subjects, Cter and intFGF-23 correlated inversely with sPi (r=−0.35, P<0.003; −0.35, P<0.003, respectively), and TmPi/GFR (r=−0.50, P<0.001; −0.54, P<0.001, respectively). In multivariate models, sPi and TmPi/GFR were independently associated with FGF-23, iPTH and eGFR. Pre-transplant iPTH levels were significantly higher in patients developing hypophosphatemia after renal transplantation. Pre-transplant levels of FGF-23 were not associated with sPi at the time of transplantation.ConclusionIn addition to PTH, elevated FGF-23 may contribute to hypophosphatemia during the early post-renal transplant period.

Type-5 Bartter syndrome presenting with metabolic seizure in adulthood

2021 ◽  
Vol 14 (2) ◽  
pp. e235349
Author(s):  
Aqeel Hussain ◽  
Mahendra Atlani ◽  
Abhishek Goyal ◽  
Alkesh Kumar Khurana
Keyword(s):  
Age Of Onset ◽  
Bartter Syndrome ◽  
Electrolyte Imbalance ◽  
Thick Ascending Limb ◽  
Calcium Sensing Receptor ◽  
Inherited Disorders ◽  
Calcium Sensing ◽  
Aged Woman ◽  
Middle Aged Woman ◽  
Renal Tubular

Bartter syndrome is a very rare and heterogeneous disease with variable age of onset and symptom severity. Genotypically they have inherited disorders of the thick ascending limb in the renal tubular system, which manifest phenotypically as electrolyte imbalance due to loss of sodium, chloride and potassium. Gain of function mutations in the calcium-sensing receptor has been described in some patients with Bartter’s syndrome (type-5 Bartter syndrome or autosomal dominant hypocalcaemia with Bartter syndrome) associated with hypocalcaemia and hypercalciuria differentiating it from Gitelman syndrome. This phenotype has been reported to present in adulthood with metabolic abnormalities. We present a case of a middle-aged woman who presented with metabolic seizures and on evaluation was found to have profound electrolyte abnormalities which were corrected with supplements and led to the resolution of symptoms.

Renal tubular reabsorption of trace alkaline earths compared with calcium

1965 ◽  
Vol 208 (6) ◽  
pp. 1165-1170 ◽  
Author(s):  
W. Joseph Rahill ◽  
Mackenzie Walser
Keyword(s):  
Protein Binding ◽  
Transport Mechanism ◽  
Tubular Reabsorption ◽  
Constant Infusion ◽  
Constant Power ◽  
Calcium Clearance ◽  
Renal Tubular Reabsorption ◽  
Order Of Magnitude ◽  
Alkaline Earths ◽  
Renal Tubular

Simultaneous clearances of inulin, calcium, and either Be7, Ba140, or Ra226, given by constant infusion, were measured in salt-depleted dogs or dogs undergoing mild saline, mannitol, or sulfate diuresis. Urine-to-plasma ratios of all three cations less than 0.5 were noted, suggesting that all can be actively reabsorbed. Clearances of barium and radium were correlated with calcium clearance, but the clearance of beryllium was unpredictable. Protein binding of beryllium was shown to be of the same order of magnitude as other alkaline earths when errors due to adsorption of Be7 onto containers were minimized. Protein binding of barium averaged 54%. The excreted-to-filtered ratio for barium was a constant power (.54) of the ratio for calcium. The data do not exclude the possibility that these cations are reabsorbed by a common transport mechanism with calcium.

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.

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