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.

Urine concentrating defect in prostaglandin EP1-deficient mice

2007 ◽  
Vol 292 (2) ◽  
pp. F868-F875 ◽  
Author(s):  
Chris R. J. Kennedy ◽  
Huaqi Xiong ◽  
Sherine Rahal ◽  
Jacqueline Vanderluit ◽  
Ruth S. Slack ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Water Channel ◽  
Significant Proportion ◽  
Plasma Osmolality ◽  
Urine Osmolality ◽  
Urine Concentration ◽  
Prostaglandin E ◽  
Rt Pcr ◽  
Urine Concentrating Ability

We investigated the role of the prostaglandin E2 (PGE2) EP1 receptor in modulating urine concentration as it is expressed along the renal collecting duct where arginine-vasopressin (AVP) exerts its anti-diuretic activity, and in the paraventricular and supraoptic nuclei of the hypothalamus where AVP is synthesized. The urine osmolality of EP1-null mice (EP1−/−) failed to match levels achieved by wild-type (WT) counterparts upon water deprivation (WD) for 24 h. This difference was reflected by higher plasma osmolality in WD EP1−/− mice. Along the collecting duct, the induction and subapical to plasma membrane translocation of the aquaporin-2 water channel in WD EP1−/− mice appeared equivalent to that of WD WT mice as determined by quantitative RT-PCR and immunohistochemistry. However, medullary interstitial osmolalities dropped significantly in EP1−/− mice following WD. Furthermore, urinary AVP levels of WD EP1−/− mice were significantly lower than those of WD WT mice. This deficit could be traced back to a blunted induction of hypothalamic AVP mRNA expression in WD EP1−/− mice as determined by quantitative RT-PCR. Administration of the AVP mimetic [deamino-Cys1,d-Arg8]-vasopressin restored a significant proportion of the urine concentrating ability of WD EP1−/− mice. When mice were water loaded to suppress endogenous AVP production, urine osmolalities increased equally for WT and EP1−/− mice. These data suggest that PGE2 modulates urine concentration by acting at EP1 receptors, not in the collecting duct, but within the hypothalamus to promote AVP synthesis in response to acute WD.

scholarly journals Aquaporin-2 downregulation in kidney medulla of aging rats is posttranscriptional and is abolished by water deprivation

2008 ◽  
Vol 294 (6) ◽  
pp. F1408-F1414 ◽  
Author(s):  
S. Combet ◽  
S. Gouraud ◽  
R. Gobin ◽  
V. Berthonaud ◽  
G. Geelen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Water Deprivation ◽  
Collecting Duct ◽  
Mrna Level ◽  
Water Channel ◽  
Urine Osmolality ◽  
Osmotic Gradient ◽  
Kidney Medulla ◽  
Aquaporin 2 ◽  
Age Related

Aging kidney is associated in humans and rodents with polyuria and reduced urine concentrating ability. In senescent female WAG/Rij rats, this defect is independent of arginine-vasopressin (AVP)/V2 receptor/cAMP pathway. It has been attributed to underexpression and mistargeting of aquaporin-2 (AQP2) water channel in the inner medullary collecting duct (IMCD). We showed previously that dDAVP administration could partially correct this defect. Since AQP2 can also be regulated by AVP-independent pathways in water deprivation (WD), we investigated AQP2 and phosphorylated AQP2 (p-AQP2) regulation in thirsted adult (10 mo old) and senescent (30 mo old) female WAG/Rij rats. Following 2-day WD, urine flow rate decreased and urine osmolality increased in both groups. However, in agreement with significantly lower cortico-papillary osmotic gradient with aging, urine osmolality remained lower in senescent animals. WD induced sixfold increase of plasma AVP in all animals which, interestingly, did not result in higher papillary cAMP level. Following WD, AQP2 and p-AQP2 expression increased hugely in 10- and 30-mo-old rats and their mistargeting in old animals was corrected. Moreover, the age-related difference in AQP2 regulation was abolished after WD. To further investigate the mechanism of AQP2 underexpression with aging, AQP2 mRNA was quantified by real-time RT-PCR. In the outer medulla, preservation of AQP2 protein expression was achieved through increased AQP2 mRNA level in senescent rats. In the IMCD, no change in AQP2 mRNA was detected with aging but AQP2 protein expression was markedly lower in 30-mo-old animals. In conclusion, there is a posttranscriptional downregulation of AQP2 with aging, which is abolished by WD.

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.

The occurrence of nephrogenic diabetes insipidus in domestic fowl

1989 ◽  
Vol 256 (4) ◽  
pp. F639-F645 ◽  
Author(s):  
E. J. Braun ◽  
J. N. Stallone
Keyword(s):  
Diabetes Insipidus ◽  
Antidiuretic Hormone ◽  
Domestic Fowl ◽  
Nephrogenic Diabetes Insipidus ◽  
Water Deprivation ◽  
Plasma Osmolality ◽  
Urine Osmolality ◽  
Arginine Vasotocin ◽  
Basal Plasma ◽  
Response To Water

Nephrogenic diabetes insipidus (NDI) results from an inability of the kidney to concentrate the urine. The underlying cause of NDI is the failure of the collecting ducts to respond to antidiuretic hormone, however, the specific tubular defect is not well understood. In the present investigation an apparent case of NDI was studied in a strain of White Leghorn domestic fowl. In this strain, water intake of the males equaled 24.0% (controls 5.4%) of their body mass (BM) per day while that of the females equaled 51.4% (controls 11.7%) of their BM per day. Plasma osmolality (mosmol/kgH2O) of the NDI birds was significantly higher than that of controls (males 319 +/- 1.7 vs. 311 +/- 1.2; females 323 +/- 1.5 vs. 310 +/- 2.2). Urine osmolality of NDI birds was substantially lower than that of controls (males 90 +/- 6.2 vs. 524 +/- 4.0; females 70 +/- 4.7 vs. no value). In response to water deprivation, plasma osmolality of the NDI birds increased more markedly than that of the control animals (males 357 +/- 2.5 vs. 331 +/- 1.2; females 375 +/- 6.0 vs. 348 +/- 1.4 at 48 h of water deprivation). Basal plasma antidiuretic hormone (plasma arginine vasotocin, PAVT) levels in male NDI birds (9.9 +/- 0.7 microU/ml) and in female NDI birds (7.0 +/- 0.5 microU/ml) were nearly sixfold or nearly threefold higher, respectively, than in control birds. In response to water deprivation, PAVT of both NDI and control birds increased to similar levels, although the absolute increases in PAVT levels were substantially less in NDI birds.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

Increased PGE2 excretion by dDAVP in humans depends on state of hydration

1986 ◽  
Vol 250 (6) ◽  
pp. F1008-F1012 ◽  
Author(s):  
U. Schwertschlag ◽  
J. G. Gerber ◽  
J. S. Barnes ◽  
A. S. Nies
Keyword(s):  
Water Deprivation ◽  
Urine Volume ◽  
Plasma Osmolality ◽  
Urine Osmolality ◽  
Water Diuresis ◽  
Water Load ◽  
Water Ingestion ◽  
Transient Rise ◽  
Relationship Of ◽  
The Relationship

The relationship of renal prostaglandin E2 (PGE2) excretion (UPGEV) to water deprivation, water diuresis, and subsequent antidiuresis by 1-desamino-8-D-arginine vasopressin (dDAVP) was studied in female volunteers. After 16 h of water deprivation, the subjects began a sustained water diuresis for 8 h. This diuresis caused a transient twofold rise in UPGEV at 2 h (P less than 0.05), which then fell back to or below baseline levels. dDAVP given during the water diuresis caused a transient rise of UPGEV as urine volume decreased and plasma osmolality fell from 277 +/- 1.5 to 271 +/- 2 mosmol/kg (P less than 0.01). Another group of subjects had the water diuresis discontinued after 4 h with dDAVP given at the 5th h when urine volume was decreasing and urine osmolality was increasing. In this setting dDAVP did not produce as great a fall in plasma osmolality nor did it increase UPGEV. These data indicate that renal prostaglandin synthesis (as determined by UPGEV) is increased transiently by an acute water load; dDAVP given during continued water ingestion results in a fall in plasma osmolality and increased PGE excretion; however, dDAVP does not increase UPGEV during normal hydration; and UPGEV is independent of changes in urine flow. These findings imply that renal prostaglandins may have a functional role in humans to inhibit the hydroosmotic actions of antidiuretic hormone, and thus hasten the excretion of a water load, and to prevent overhydration when inappropriate antidiuresis occurs. However, there is no evidence that the stimulus for prostaglandin production is dDAVP per se.

Normal Urine Concentrating Ability in Magnesium Depletion

1972 ◽  
Vol 43 (6) ◽  
pp. 723-729 ◽  
Author(s):  
S. M. Suh ◽  
J. Sellors
Keyword(s):  
Water Deprivation ◽  
Urine Osmolality ◽  
Urine Concentration ◽  
Potassium Depletion ◽  
Magnesium Depletion ◽  
Normal Urine ◽  
Urine Concentrating Ability

1. We studied urine concentrating ability in ten magnesium-depleted puppies and compared the results with those of match-fed, littermate controls. 2. The experimental puppies became hypomagnesaemic and hypocalcaemic without evidence of potassium depletion. After 24 h of food and water deprivation, urine osmolality increased to 1350 ± 340 mosm/kg of water. This value did not differ from that of control animals. 3. We also studied urine concentrating ability in a child with primary hypomagnesaemia and secondary hypocalcaemia. He could achieve a urine concentration of 1080 mosm/kg of water after 20 h of water deprivation when he was hypomagnesaemic and hypocalcaemic. 4. We conclude that urine concentrating ability is normal in magnesium depletion uncomplicated by hypercalcaemia or severe potassium depletion.

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