Urine-concentrating defects exacerbate with age in male offspring with a low-nephron endowment

2011 ◽  
Vol 301 (6) ◽  
pp. F1168-F1176 ◽  
Author(s):  
Reetu R. Singh ◽  
Kate M. Denton ◽  
John F. Bertram ◽  
John Dowling ◽  
Karen M. Moritz
Keyword(s):  
Water Deprivation ◽  
Sham Group ◽  
Chronic Renal Disease ◽  
Urine Osmolality ◽  
Treatment Groups ◽  
Nephron Endowment ◽  
Renal Expression ◽  
Male Sheep ◽  
Urine Concentrating Ability ◽  
Concentrating Defect

Fetal uninephrectomy (uni-x) in male sheep at 100 days of gestation (term = 150 days) reduces overall nephron endowment without affecting birth weight. Offspring have a lower glomerular filtration rate (GFR) and elevated mean arterial pressure (MAP) at 6 mo of age. This study investigated whether this reduction in renal function was associated with impaired urine-concentrating ability at 6 mo of age and exacerbated with ageing (4 yr) and examined response to 1) nonpressor dose of exogenous arginine vasopressin (AVP; 0.2 μg·kg−1·h−1 iv) and 2) 30 h of water deprivation. Basal MAP was higher in uni-x animals at both ages, and became further elevated with age compared with the sham group (elevation in MAP with age; sham: ∼4 mmHg, uni-x: 9 mmHg, Pgroup × age < 0.01). GFR declined with ageing in both groups with the decrease being greater with age in the uni-x group (further 26%, Pgroup × age < 0.001). In response to AVP infusion, urine osmolality increased in both treatment groups; this response was significantly lower in the uni-x animals and became further reduced with ageing. Uni-x animals had reduced renal expression of vasopressin-2 receptor and aquaporin-2 at both ages ( P < 0.01). The increase in plasma AVP levels in response to dehydration was similar between the treatment groups, suggesting the urine-concentrating defect was associated with these renal gene changes rather than defects in AVP secretion. Renal insufficiency due to a low-nephron endowment increases the risk of hypertension and chronic renal disease and may incur greater vulnerability to physiological challenges such as water deprivation as observed in the uni-x animals.

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 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.

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.

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.

scholarly journals Urea and urine concentrating ability in mice lacking AQP1 and AQP3

2006 ◽  
Vol 291 (2) ◽  
pp. F429-F438 ◽  
Author(s):  
Dan Zhao ◽  
Lise Bankir ◽  
Liman Qian ◽  
Dayu Yang ◽  
Baoxue Yang
Keyword(s):  
Time Course ◽  
Critical Role ◽  
Urine Volume ◽  
Urine Osmolality ◽  
Solute Concentration ◽  
Urea Concentration ◽  
Wild Type ◽  
Concentrate Urea ◽  
Urine Concentrating Ability ◽  
Concentrating Defect

Aquaporin-1 (AQP1) and aquaporin-3 (AQP3) water channels expressed in the kidney play a critical role in the urine concentrating mechanism. Mice with AQP1 or AQP3 deletion have a urinary concentrating defect. To better characterize this defect, we studied the influence of an acute urea load (300 μmol ip) in conscious AQP1-null, AQP3-null, and wild-type mice. Urine was collected and assayed every 2 h, from 2 h before (baseline) to 8 h after the urea load. Mice of all genotypes excreted the urea load in ∼4 h with the same time course. Interestingly, despite their low baseline, the AQP3-null mice raised their urine osmolality and urea concentration progressively after the urea load to values almost equal to those in wild-type mice at 8 h. In contrast, urine non-urea solute concentration did not change. Urine volume fell in the last 4 h to about one-fourth of basal values. AQP1-null mice increased their urine flow rate much more than AQP3-null mice and showed no change in urine osmolality and urea concentration. The urea load strongly upregulated urea transporter UT-A3 expression in all three genotypes. These observations show that the lack of AQP3 does not interfere with the ability of the kidney to concentrate urea but impairs its ability to concentrate other solutes. This solute-selective response could result from the capacity of AQP3 to transport not only water but also urea. The results suggest a novel role for AQP3 in non-urea solute concentration in the urine.

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 USE OF CHLORPROPAMIDE IN DIABETES INSIPIDUS IN CHILDREN

PEDIATRICS ◽  
1970 ◽  
Vol 45 (2) ◽  
pp. 236-245
Author(s):  
Robert M. Ehrlich ◽  
Sang Whay Kooh
Keyword(s):  
Diabetes Insipidus ◽  
Water Deprivation ◽  
Plasma Insulin ◽  
Urine Volume ◽  
Insulin Response ◽  
Urine Osmolality ◽  
Post Traumatic ◽  
Term Management ◽  
Plasma Insulin Response

Oral chlorpropamide was administered to 17 children with diabetes insipidus (D.I.). The cause of the D.I. was idiopathic, six; histiocytosis, five; craniopharyngioma, three; pinealoma, two, and post-traumatic, one. Twenty-four-hour urine volume and measurements of serum and urine osmolality at the beginning and end of a 7-hour water deprivation test were used to evaluatechlorpropamide therapy. Administration of 150 to 400 mg of chlorpropamide per day by mouth caused a reduction in urine volume in all patients (range 8 to 67%). No change in aldosterone, 17-hydroxycorticoids, or electrolyte excretion was noted. Serum electrolytes and glomerular filtration rate were not affected by therapy. Glucose tolerance and plasma insulin response remained normal in those patients tested. Mild leucine sensitivity without significant change in plasma insulin was induced in four children. During water deprivation, seven patients with secondary D.I. but only one with idiopathic D.I. produced hypertonic urine. Hypoglycemia developed in seven children and is the major hazard of treatment. Long-term management of D.I. has been possible in nine children. Oral chlorpropamide is a useful drug in children with vasopressin-sensitive diabetes insipidus.

Effect of water restriction on urinary concentrating ability of K-depleted rats

1960 ◽  
Vol 199 (5) ◽  
pp. 912-914 ◽  
Author(s):  
William B. Blythe ◽  
Margaret Newton ◽  
Fernando Lazcano ◽  
Louis G. Welt
Keyword(s):  
Water Intake ◽  
The Other ◽  
Potassium Depletion ◽  
Water Restriction ◽  
Control Groups ◽  
Ad Libitum ◽  
Urinary Concentrating Ability ◽  
Excessive Water ◽  
Urine Concentrating Ability ◽  
Concentrating Defect

In order to test the possibility that the urinary concentrating defect associated with potassium depletion results from excessive water intake that accompanies potassium depletion, water intake was restricted in one half of a group of rats undergoing potassium depletion. The other one half of the group was allowed to drink ad libitum After 14 days, ability to concentrate the urine was tested in both groups as well as in two groups of control rats, one of which was allowed to drink ad libitum and the other having water intake restricted. Although both potassium-depleted groups concentrated urine less than the control groups, there was no difference in urine-concentrating ability between the two potassium-depleted groups. It is concluded that the urinary concentrating defect in potassium depletion is not due to excessive water intake.

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.

Water Balance and Kidney Function in Four Species of Rattus From Ecologically Diverse Environments.

1976 ◽  
Vol 24 (1) ◽  
pp. 7 ◽  
Author(s):  
PR Baverstock
Keyword(s):  
Drinking Water ◽  
Water Balance ◽  
Osmotic Pressure ◽  
Individual Variation ◽  
Water Deprivation ◽  
High Metabolic Rate ◽  
Sodium Potassium ◽  
Rattus Fuscipes ◽  
Microhabitat Preferences ◽  
Urine Concentrating Ability

While Rattus fuscipes survived only 4 days of water deprivation at 21�C, R. norvegicus, R. villosissimus and R. lutreolus survived 13-16 days. There was considerable inter-individual variation in the response of water-deprived R. villosissimus. Analysis of osmotic pressure, urea, sodium, potassium and chloride of both plasma and urine of rats with and without drinking water revealed that: (1) the abilities of R. norvegicus and R. villosissimus to tolerate water deprivation were due in large part to their abilities to produce highly concentrated urine; (2) R. lutreolus tolerated long periods of water deprivation not by urine-concentrating ability but by partly abandoning homeostasis and tolerating elevated levels of plasma solutes; (3) water-deprived R. fuscipes excreted large volumes of concentrated urine, possibly because their relatively high metabolic rate necessitated the excretion of excess metabolites. In all of the rats, urea constituted an unusually low proportion of the total osmotic pressure. The water-balance response of water-deprived rats is at variance with both their macrogeographical distribution and microhabitat preferences.

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