Mice with targeted disruption of the acyl-CoA binding protein display attenuated urine concentrating ability and diminished renal aquaporin-3 abundance

2012 ◽  
Vol 302 (8) ◽  
pp. F1034-F1044 ◽  
Author(s):  
Stine Langaa ◽  
Maria Bloksgaard ◽  
Signe Bek ◽  
Ditte Neess ◽  
Rikke Nørregaard ◽  
...  
Keyword(s):  
Water Deprivation ◽  
Binding Protein ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Plasma Concentrations ◽  
Relative Weight ◽  
Urine Osmolality ◽  
Cell Types ◽  
Targeted Disruption ◽  
Urine Concentrating Ability

The acyl-CoA binding protein (ACBP) is a small intracellular protein that specifically binds and transports medium to long-chain acyl-CoA esters. Previous studies have shown that ACBP is ubiquitously expressed but found at particularly high levels in lipogenic cell types as well as in many epithelial cells. Here we show that ACBP is widely expressed in human and mouse kidney epithelium, with the highest expression in the proximal convoluted tubules. To elucidate the role of ACBP in the renal epithelium, mice with targeted disruption of the ACBP gene (ACBP−/−) were used to study water and NaCl balance as well as urine concentrating ability in metabolic cages. Food intake and urinary excretion of Na+ and K+ did not differ between ACBP−/− and +/+ mice. Interestingly, however, water intake and diuresis were significantly higher at baseline in ACBP−/− mice compared with that of +/+ mice. Subsequent to 20-h water deprivation, ACBP−/− mice exhibited increased diuresis, reduced urine osmolality, elevated hematocrit, and higher relative weight loss compared with +/+ mice. There were no significant differences in plasma concentrations of renin, corticosterone, and aldosterone between mice of the two genotypes. After water deprivation, renal medullary interstitial fluid osmolality and concentrations of Na+, K+, and urea did not differ between genotypes and cAMP excretion was similar. Renal aquaporin-1 (AQP1), -2, and -4 protein abundances did not differ between water-deprived +/+ and ACBP−/− mice; however, ACBP−/− mice displayed increased apical targeting of pS256-AQP2. AQP3 abundance was lower in ACBP−/− mice than in +/+ control animals. Thus we conclude that ACBP is necessary for intact urine concentrating ability. Our data suggest that the deficiency in urine concentrating ability in the ACBP−/− may be caused by reduced AQP3, leading to impaired efflux over the basolateral membrane of the collecting duct.

COX-2 disruption leads to increased central vasopressin stores and impaired urine concentrating ability in mice

2011 ◽  
Vol 301 (6) ◽  
pp. F1303-F1313 ◽  
Author(s):  
Rikke Nørregaard ◽  
Kirsten Madsen ◽  
Pernille B. L. Hansen ◽  
Peter Bie ◽  
Sugarna Thavalingam ◽  
...  
Keyword(s):  
Water Deprivation ◽  
Collecting Duct ◽  
Mrna Level ◽  
Plasma Osmolality ◽  
Urine Osmolality ◽  
Glomerular Injury ◽  
Plasma Urea ◽  
Cox 2 ◽  
Response To Water ◽  
Urine Concentrating Ability

It was hypothesized that cyclooxygenase-2 (COX-2) activity promotes urine concentrating ability through stimulation of vasopressin (AVP) release after water deprivation (WD). COX-2-deficient (COX-2−/−, C57BL/6) and wild-type (WT) mice were water deprived for 24 h, and water balance, central AVP mRNA and peptide level, AVP plasma concentration, and AVP-regulated renal transport protein abundances were measured. In male COX-2−/−, basal urine output and water intake were elevated while urine osmolality was decreased compared with WT. Water deprivation resulted in lower urine osmolality, higher plasma osmolality in COX-2−/− mice irrespective of gender. Hypothalamic AVP mRNA level increased and was unchanged between COX-2−/− and WT after WD. AVP peptide content was higher in COX-2−/− compared with WT. At baseline, plasma AVP concentration was elevated in conscious chronically catheterized COX-2−/− mice, but after WD plasma AVP was unchanged between COX-2−/− and WT mice (43 ± 11 vs. 70 ± 16 pg/ml). Renal V2 receptor abundance was downregulated in COX-2−/− mice. Medullary interstitial osmolality increased and did not differ between COX-2−/− and WT after WD. Aquaporin-2 (AQP2; cortex-outer medulla), AQP3 (all regions), and UT-A1 (inner medulla) protein abundances were elevated in COX-2−/− at baseline and further increased after WD. COX-2−/− mice had elevated plasma urea and creatinine and accumulation of small subcapsular glomeruli. In conclusion, hypothalamic COX-2 activity is not necessary for enhanced AVP expression and secretion in response to water deprivation. Renal medullary COX-2 activity negatively regulates AQP2 and -3. The urine concentrating defect in COX-2−/− is likely caused by developmental glomerular injury and not dysregulation of AVP or collecting duct aquaporins.

Sex difference in urinary concentrating ability of rats with water deprivation

1996 ◽  
Vol 270 (3) ◽  
pp. R550-R555 ◽  
Author(s):  
Y. X. Wang ◽  
J. T. Crofton ◽  
J. Miller ◽  
C. J. Sigman ◽  
H. Liu ◽  
...  
Keyword(s):  
Water Deprivation ◽  
Plasma Concentrations ◽  
Plasma Osmolality ◽  
Urine Osmolality ◽  
Ovarian Hormones ◽  
Urine Flow ◽  
The Other ◽  
Consumptive Behavior ◽  
Urinary Concentrating Ability ◽  
Previous Demonstration

Our previous demonstration of sexual dimorphism in the antidiuretic response to exogenous vasopressin prompted us to investigate the response to moderately high levels of endogenous vasopressin stimulated by water deprivation in conscious rats. After 24 h water deprivation, urine flow was significantly higher and urine osmolality lower in females than in males. Plasma concentrations of vasopressin were higher in females than in males after water deprivation, but plasma osmolality did not differ. Gonadectomy, which had no effect in dehydrated males, decreased urine flow and increased urine osmolality in females to levels observed in intact and gonadectomized males. Spontaneous water intake was also measured and found to be lower in males and estrous females than in females in the other phases of the estrous cycle. These observations support the concept that there is a gender difference in the antidiuretic responsiveness to endogenous vasopressin, that this difference is dependent upon the ovarian hormones, and that it may lead to differences in consumptive behavior.

Phenotypic plasticity in the intercalated cell: the hensin pathway

1998 ◽  
Vol 275 (2) ◽  
pp. F183-F190 ◽  
Author(s):  
Qais Al-Awqati ◽  
S. Vijayakumar ◽  
C. Hikita ◽  
J. Chen ◽  
J. Takito
Keyword(s):  
Collecting Duct ◽  
Basolateral Membrane ◽  
Cell Types ◽  
Band 3 ◽  
Cytoskeletal Proteins ◽  
Β Cell ◽  
Biochemical Basis ◽  
Intercalated Cell ◽  
Immortalized Cell

The collecting duct of the renal tubule contains two cell types, one of which, the intercalated cell, is responsible for acidification and alkalinization of urine. These cells exist in a multiplicity of morphological forms, with two extreme types, α and β. The former acidifies the urine by an apical proton-translocating ATPase and a basolateral Cl/HCO3 exchanger, which is an alternately spliced form of band 3. This kidney form of band 3, kAE1, is present in the apical membrane of the β-cell, which has the H+-ATPase on the basolateral membrane. We had suggested previously that metabolic acidosis leads to conversion of β-types to α-types. To study the biochemical basis of this plasticity, we used an immortalized cell line of the β-cell and showed that these cells convert to the α-phenotype when plated at superconfluent density. At high density these cells localize a new protein, which we term “hensin,” to the extracellular matrix, and hensin acts as a molecular switch capable of changing the phenotype of these cells in vitro. Hensin induces new cytoskeletal proteins, makes the cells assume a more columnar shape and retargets kAE1 and the H+-ATPase. These recent studies suggest that the conversion of β- to α-cells, at least in vitro, bears many of the hallmarks of terminal differentiation.

Functional characterization of alpha- and beta-intercalated cell types in rabbit cortical collecting duct

1991 ◽  
Vol 261 (3) ◽  
pp. F377-F385 ◽  
Author(s):  
H. Furuya ◽  
M. D. Breyer ◽  
H. R. Jacobson
Keyword(s):  
Collecting Duct ◽  
Basolateral Membrane ◽  
Functional Characterization ◽  
Cell Types ◽  
Disulfonic Acid ◽  
Cortical Collecting Duct ◽  
Electrical Measurements ◽  
Collecting Ducts

Single-cell electrical measurements and spectrophotometric determinations of intracellular pH were used to determine unique features of alpha- and beta-intercalated cells (alpha-IC, beta-IC) in in vitro perfused rabbit cortical collecting ducts (CCD). pHi rose in alpha-IC and fell in beta-IC after bath Cl- removal. Luminal Cl- removal did not change pHi of alpha-IC, but pHi of beta-IC rose by 0.36 +/- 0.01 pH units. Cl- concentration-dependent recovery of beta-IC pHi revealed a Cl- Km of 18.7 mM for the luminal Cl(-) -HCO3- exchanger. Measurements of basolateral membrane voltage (Vbl) also showed two IC cell types. Removal of luminal Cl- did not change Vbl in alpha-IC, whereas Vbl hyperpolarized by a mean of 73.2 +/- 3.5 mV in beta-IC. Reducing bath Cl- depolarized both alpha- and beta-IC Vbl. In alpha-IC a large repolarization of 39.8 +/- 5.2 mV followed acute depolarization after bath Cl- removal. Reducing bath HCO3- (constant CO2) had little effect on beta-IC Vbl, whereas alpha-IC Vbl depolarized by 5.2 +/- 0.7 mV. Reducing luminal HCO3- in the absence of luminal Cl- produced a 17.6 +/- 1.8 mV depolarization in beta-IC. This change was independent of luminal Na+ and was not blocked by luminal 10(-4) M 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). In beta-IC, Vbl was not altered by either bath or lumen DIDS in the presence of luminal Cl-. However, when luminal Cl- was removed, luminal DIDS reversibly depolarized Vbl by 9.6 +/- 2.9 mV.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Lithium-induced NDI: acetazolamide reduces polyuria but does not improve urine concentrating ability

2017 ◽  
Vol 313 (3) ◽  
pp. F669-F676 ◽  
Author(s):  
Theun de Groot ◽  
Joan Doornebal ◽  
Birgitte M. Christensen ◽  
Simone Cockx ◽  
Anne P. Sinke ◽  
...  
Keyword(s):  
Urine Output ◽  
Nephrogenic Diabetes Insipidus ◽  
Filtration Rate ◽  
Collecting Duct ◽  
Urine Osmolality ◽  
Systemic Blood Pressure ◽  
Systemic Blood ◽  
Urine Concentrating Ability ◽  
Concentrating Defect

Lithium is the mainstay treatment for patients with bipolar disorder, but it generally causes nephrogenic diabetes insipidus (NDI), a disorder in which the renal urine concentrating ability has become vasopressin insensitive. Li-NDI is caused by lithium uptake by collecting duct principal cells and downregulation of aquaporin-2 (AQP2) water channels, which are essential for water uptake from tubular urine. Recently, we found that the prophylactic administration of acetazolamide to mice effectively attenuated Li-NDI. To evaluate whether acetazolamide might benefit lithium-treated patients, we administered acetazolamide to mice with established Li-NDI and six patients with a lithium-induced urinary concentrating defect. In mice, acetazolamide partially reversed lithium-induced polyuria and increased urine osmolality, which, however, did not coincide with increased AQP2 abundances. In patients, acetazolamide led to the withdrawal of two patients from the study due to side effects. In the four remaining patients acetazolamide did not lead to clinically relevant changes in maximal urine osmolality. Urine output was also not affected, although none of these patients demonstrated overt lithium-induced polyuria. In three out of four patients, acetazolamide treatment increased serum creatinine levels, indicating a decreased glomerular filtration rate (GFR). Strikingly, these three patients also showed a decrease in systemic blood pressure. All together, our data reveal that acetazolamide does not improve the urinary concentrating defect caused by lithium, but it lowers the GFR, likely explaining the reduced urine output in our mice and in a recently reported patient with lithium-induced polyuria. The reduced GFR in patients prone to chronic kidney disease development, however, warrants against application of acetazolamide in Li-NDI patients without long-term (pre)clinical studies.

scholarly journals Race, sex, and the regulation of urine osmolality: observations made during water deprivation

2010 ◽  
Vol 299 (3) ◽  
pp. R977-R980 ◽  
Author(s):  
Michael L. Hancock ◽  
Daniel G. Bichet ◽  
George J. Eckert ◽  
Lise Bankir ◽  
Mary Anne Wagner ◽  
...  
Keyword(s):  
Water Conservation ◽  
Water Deprivation ◽  
Collecting Duct ◽  
Urine Osmolality ◽  
Thick Ascending Limb ◽  
Race Difference ◽  
Water Reabsorption ◽  
Blacks And Whites ◽  
Relationship Of ◽  
The Relationship

A more concentrated urine is excreted by blacks than whites and by men than women. The purpose of this study was to explore the physiological bases for the race and sex effects during water deprivation when osmoregulation is challenged and differences are amplified. Drinking water was withheld from 17 blacks (10 men) and 19 whites (9 men) for 24 h. Vasopressin (VP) levels and osmolality in plasma (Posmol) and urine (Uosmol) were measured basally and then every 4 h. Uosmol was higher in blacks at baseline ( P = 0.01) and during water deprivation ( P = 0.046). Before and during water deprivation, no differences were seen in levels of VP, Posmol, or the VP-Uosmol relationship between blacks and whites. Although VP levels were initially higher in men ( P < 0.02 for samples collected over the first 12 h), over the last 12 h of water deprivation, Uosmol was higher ( P = 0.027) and more responsive to the level of VP (in terms of slopes, P = 0.0001) in women than men. Our results suggest that, after a period of water deprivation, there develops a sensitivity of the collecting duct to VP that is greater in women. Although Uosmol is higher in blacks, the race difference in water conservation did not appear to result from differences in the level of VP or the sensitivity of the collecting duct to VP. Upstream effects such as Na+ uptake in the thick ascending limb, with its ensuing effects on water reabsorption, need to be considered in future studies of the relationship of race to water conservation.

Cl- current in IMCD cells activated by hypotonicity: time course, ATP dependence, and inhibitors

1996 ◽  
Vol 271 (3) ◽  
pp. F552-F559 ◽  
Author(s):  
K. A. Volk ◽  
C. Zhang ◽  
R. F. Husted ◽  
J. B. Stokes
Keyword(s):  
Time Course ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Primary Cultures ◽  
Renal Medulla ◽  
Cell Types ◽  
Disulfonic Acid ◽  
Patch Clamp Technique ◽  
Whole Cell Patch Clamp ◽  
Voltage Dependent

The hypertonic environment of the renal medulla can change rapidly according to the state of hydration of the animal. We used primary cultures of rat inner medullary collecting duct (IMCD) cells to investigate the characteristics of Cl- currents activated by an acute reduction in osmolarity (ICl(osm)). Using the whole cell patch-clamp technique, we identified an outwardly rectifying current that decayed slowly at strongly depolarizing voltages. The onset of ICl(osm) began 6.7 min after the fall in bath osmolarity, a delay longer than reported in other cell types. Hypotonicity did not induce an increase in intracellular Ca2+ concentration, and activation of ICl(osm) did not require the presence of Ca2+. Intracellular ATP was needed to evoke ICl(osm) when the hypotonic stimulus was modest (50 mosmol/l or less) but was not necessary when the stimulus was stronger (100 mosmol/ l). ICl(osm) was inhibited by 5-nitro-2-(3-phenylpropylamino)benzoic acid but not by tamoxifen or glibenclamide. 4,4'-Diisothiocyanostilbene-2,2'-disulfonic acid produced a voltage-dependent block. Acute reduction in osmolarity using cells grown on filters did not induce a Cl- secretory current. The ICl(osm) of IMCD cells appears to be on the basolateral membrane and displays some unique features.

Interaction of Cl- and other halogens with Cl- transport systems in rabbit cortical collecting duct

1992 ◽  
Vol 263 (5) ◽  
pp. F870-F877 ◽  
Author(s):  
S. Muto ◽  
M. Imai ◽  
Y. Asano
Keyword(s):  
Apical Membrane ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Cell Types ◽  
Transport Systems ◽  
Cortical Collecting Duct ◽  
Cl Transport ◽  
Distinct Cell ◽  
Cl Conductance ◽  
Basolateral Membrane Potential

We have reported that in the rabbit cortical collecting duct (CCD) we can identify electrophysiologically three distinct cell types; the collecting duct (CD) cell and the alpha- and beta-intercalated (IC) cell. To further characterize the Cl- transport properties of each cell type, we examined the interaction between Cl- and other halogens or SCN- in the isolated and perfused CCD by intracellular microelectrode impalement. The rapid depolarization of the basolateral membrane potential (VB) caused by replacement of bath Cl- with each anion revealed that the sequences of apparent halogen selectivity for the basolateral Cl- conductance were similar in all three cell types. The ranking of Cl- > Br- > F- > I- corresponds to the sequence 5 of Eisenman's series, indicating “strong” interaction of the anions with the selectivity site. The basolateral Cl- conductance of these three cell types may share common characteristics, although I- permeability is less in IC cells than in CD cells. Hyperpolarization of the basolateral membrane of the beta-IC cell upon reduction of luminal Cl- reflects alterations in either Cl- entry across the apical membrane, or Cl- exit across the basolateral membrane, or both. Luminal Cl- replacement with each anion showed that the sequence of the hyperpolarization of the basolateral membrane was I- >> cyclamate = SCN- > F- > Br-, suggesting that I-inhibits either apical Cl- entry or basolateral Cl- exit. On the other hand, in the CD cell reduction of the perfusate Cl- by replacement with each anion caused the basolateral membrane to hyperpolarize with a different ranking: cyclamate = F- > I- = SCN- > Br-.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals mPGES-1 deletion potentiates urine concentrating capability after water deprivation

2012 ◽  
Vol 302 (8) ◽  
pp. F1005-F1012 ◽  
Author(s):  
Zhanjun Jia ◽  
Gang Liu ◽  
Maicy Downton ◽  
Zheng Dong ◽  
Aihua Zhang ◽  
...  
Keyword(s):  
Water Deprivation ◽  
Potential Role ◽  
Urine Volume ◽  
Renal Medulla ◽  
Urine Osmolality ◽  
Protein Abundance ◽  
Wild Type ◽  
Control Groups ◽  
Urine Concentrating Ability

PGE2 plays an important role in the regulation of fluid metabolism chiefly via antagonizing vasopressin-induced osmotic permeability in the distal nephron, but its enzymatic sources remain uncertain. The present study was undertaken to investigate the potential role of microsomal PGE synthase (mPGES)-1 in the regulation of urine concentrating ability after water deprivation (WD). Following 24-h WD, wild-type (WT) mice exhibited a significant reduction in urine volume, accompanied by a significant elevation in urine osmolality compared with control groups. In contrast, in response to WD, mPGES-1 knockout (KO) mice had much less urine volume and higher urine osmolality. Analysis of plasma volume by measurement of hematocrit and by using a nanoparticle-based method consistently demonstrated that dehydrated WT mice were volume depleted, which was significantly improved in the KO mice. WD induced a twofold increase in urinary PGE2 output in WT mice, which was completely blocked by mPGES-1 deletion. At baseline, the KO mice had a 20% increase in V2 receptor mRNA expression in the renal medulla but not the cortex compared with WT controls; the expression was unaffected by WD irrespective of the genotype. In response to WD, renal medullary aquaporin-2 (AQP2) mRNA exhibited a 60% increase in WT mice, and this increase was greater in the KO mice. Immunoblotting demonstrated increased renal medullary AQP2 protein abundance in both genotypes following WD, with a greater increase in the KO mice. Similar results were obtained by using immunohistochemistry. Paradoxically, plasma AVP response to WD seen in WT mice was absent in the KO mice. Taken together, these results suggest that mPGES-1-derived PGE2 reduces urine concentrating ability through suppression of renal medullary expression of V2 receptors and AQP2 but may enhance it by mediating the central AVP response.

Similar chloride channels in the connecting tubule and cortical collecting duct of the mouse kidney

2006 ◽  
Vol 290 (6) ◽  
pp. F1421-F1429 ◽  
Author(s):  
Antoine Nissant ◽  
Marc Paulais ◽  
Sahran Lachheb ◽  
Stéphane Lourdel ◽  
Jacques Teulon
Keyword(s):  
Chloride Channels ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Reversal Potential ◽  
Cell Types ◽  
Cortical Collecting Duct ◽  
Patch Clamp Technique ◽  
Connecting Tubule ◽  
Recording Conditions ◽  
Rich Solution

Using the patch-clamp technique, we investigated Cl− channels on the basolateral membrane of the connecting tubule (CNT) and cortical collecting duct (CCD). We found a ∼10-pS channel in CNT cell-attached patches. Substitution of sodium gluconate for NaCl in the pipette shifted the reversal potential by +25 mV, whereas N-methyl-d-gluconate chloride had no effect, indicating anion selectivity. On inside-out patches, we determined a selectivity sequence of Cl− > Br− ∼ NO3− > F−, which is compatible with that of ClC-K2, a Cl− channel in the distal nephron. In addition, the number of open channels ( NPo) measured in cell-attached patches was significantly increased when Ca2+ concentration or pH in the pipette was increased, which is another characteristic of ClC-K. These findings suggest that the basis for this channel is ClC-K2. A similar Cl− channel was found in CCD patches. Because CNT and CCD are heterogeneous tissues, we studied the cellular distribution of the Cl− channel using recording conditions (KCl-rich solution in the pipette) that allowed us to detect simultaneously Cl− channels and inwardly rectifying K+ channels. We detected Cl− channels alone in 45% and 42% and K+ channels alone in 51% and 58% of CNT and CCD patches, respectively. Cl− and K+ channels were recorded simultaneously from two patches (4% of patches) in the CNT and from none of the patches in the CCD. This indicates that Cl− and K+ channels are located in different cell types, which we suggest may be the intercalated cells and principal cells, respectively.

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