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

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.

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

AJP Renal Physiology ◽

10.1152/ajprenal.1986.250.6.f1008 ◽

1986 ◽

Vol 250 (6) ◽

pp. F1008-F1012 ◽

Cited By ~ 1

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.

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Genetic deletion of connexin 37 causes polyuria and polydipsia

PLoS ONE ◽

10.1371/journal.pone.0244251 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0244251

Author(s):

Jianxiang Xue ◽

Linto Thomas ◽

Jessica A. Dominguez Rieg ◽

Robert A. Fenton ◽

Timo Rieg

Keyword(s):

Water Deprivation ◽

Fluid Intake ◽

Collecting Duct ◽

Urine Osmolality ◽

Physiological Data ◽

Thick Ascending Limb ◽

Renal Vasculature ◽

Paracrine Factors ◽

Water Handling ◽

Connexin 37

The connexin 37 (Cx37) channel is clustered at gap junctions between cells in the renal vasculature or the renal tubule where it is abundant in basolateral cell interdigitations and infoldings of epithelial cells in the proximal tubule, thick ascending limb, distal convoluted tubule and collecting duct; however, physiological data regarding its role are limited. In this study, we investigated the role of Cx37 in fluid homeostasis using mice with a global deletion of Cx37 (Cx37-/- mice). Under baseline conditions, Cx37-/- had ~40% higher fluid intake associated with ~40% lower urine osmolality compared to wild-type (WT) mice. No differences were observed between genotypes in urinary adenosine triphosphate or prostaglandin E2, paracrine factors that alter renal water handling. After 18-hours of water deprivation, plasma aldosterone and urine osmolality increased significantly in Cx37-/- and WT mice; however, the latter remained ~375 mmol/kg lower in Cx37-/- mice, an effect associated with a more pronounced body weight loss despite higher urinary AVP/creatinine ratios compared to WT mice. Consistent with this, fluid intake in the first 3 hours after water deprivation was 37% greater in Cx37-/- vs WT mice. Cx37-/- mice showed significantly lower renal AQP2 abundance and AQP2 phosphorylation at serine 256 than WT mice in response to vehicle or dDAVP, suggesting a partial contribution of the kidney to the lower urine osmolality. The abundance and responses of the vasopressin V2 receptor, AQP3, NHE3, NKCC2, NCC, H+-ATPase, αENaC, γENaC or Na+/K+-ATPase were not significantly different between genotypes. In summary, these results demonstrate that Cx37 is important for body water handling.

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Demonstration of the functional impact of vasopressin signaling in the thick ascending limb by a targeted transgenic rat approach

AJP Renal Physiology ◽

10.1152/ajprenal.00126.2016 ◽

2016 ◽

Vol 311 (2) ◽

pp. F411-F423 ◽

Cited By ~ 13

Author(s):

Kerim Mutig ◽

Tordis Borowski ◽

Christin Boldt ◽

Aljona Borschewski ◽

Alexander Paliege ◽

...

Keyword(s):

Epithelial Transport ◽

Collecting Duct ◽

Surface Expression ◽

Urine Concentration ◽

Dominant Negative ◽

Transgenic Rat ◽

Thick Ascending Limb ◽

Water Reabsorption ◽

Mediated Effects ◽

Response To Water

The antidiuretic hormone vasopressin (AVP) regulates renal salt and water reabsorption along the distal nephron and collecting duct system. These effects are mediated by vasopressin 2 receptors (V2R) and release of intracellular Gs-mediated cAMP to activate epithelial transport proteins. Inactivating mutations in the V2R gene lead to the X-linked form of nephrogenic diabetes insipidus (NDI), which has chiefly been related with impaired aquaporin 2-mediated water reabsorption in the collecting ducts. Previous work also suggested the AVP-V2R-mediated activation of Na+-K+-2Cl−-cotransporters (NKCC2) along the thick ascending limb (TAL) in the context of urine concentration, but its individual contribution to NDI or, more generally, to overall renal function was unclear. We hypothesized that V2R-mediated effects in TAL essentially determine its reabsorptive function. To test this, we reevaluated V2R expression. Basolateral membranes of medullary and cortical TAL were clearly stained, whereas cells of the macula densa were unreactive. A dominant-negative, NDI-causing truncated V2R mutant (Ni3-Glu242stop) was then introduced into the rat genome under control of the Tamm-Horsfall protein promoter to cause a tissue-specific AVP-signaling defect exclusively in TAL. Resulting Ni3-V2R transgenic rats revealed decreased basolateral but increased intracellular V2R signal in TAL epithelia, suggesting impaired trafficking of the receptor. Rats displayed significant baseline polyuria, failure to concentrate the urine in response to water deprivation, and hypercalciuria. NKCC2 abundance, phosphorylation, and surface expression were markedly decreased. In summary, these data indicate that suppression of AVP-V2R signaling in TAL causes major impairment in renal fluid and electrolyte handling. Our results may have clinical implications.

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Reduced AQP1, -2, and -3 levels in kidneys of rats with CRF induced by surgical reduction in renal mass

AJP Renal Physiology ◽

10.1152/ajprenal.1998.275.5.f724 ◽

1998 ◽

Vol 275 (5) ◽

pp. F724-F741 ◽

Cited By ~ 27

Author(s):

Tae-Hwan Kwon ◽

Jørgen Frøkiaer ◽

Mark A. Knepper ◽

Søren Nielsen

Keyword(s):

Urine Output ◽

Renal Mass ◽

Collecting Duct ◽

Free Water ◽

Urine Osmolality ◽

Urinary Concentration ◽

Water Reabsorption ◽

Similar Reduction ◽

Urine Production ◽

Quantitative Immunoblotting

Urinary concentration characteristically decreases in response to a reduction in renal mass in chronic renal failure (CRF). In the present study, we examined whether there are changes in the expression of aquaporins in rats where CRF was induced by 5/6 nephrectomy. Plasma creatinine levels were significantly elevated consistent with significant CRF: 135.7 ± 15.1 ( n = 17, CRF) vs. 33.9 ± 1.1 μmol/l ( n = 11, sham), P < 0.05. Two weeks after 5/6 nephrectomy, the remnant kidneys were hypertrophied, and total renal mass increased to 65 ± 3% of sham levels ( P < 0.05). Urine production increased markedly from 40 ± 2 to 111 ± 3 μl ⋅ min−1 ⋅ kg−1in CRF rats ( P < 0.05), whereas urine osmolality and solute-free water reabsorption decreased significantly. Quantitative immunoblotting of total kidney membrane fractions revealed a significant decrease in total kidney AQP2 expression in CRF rats to 43 ± 12% of sham levels ( P < 0.05). A similar reduction was observed for AQP1 and AQP3. Furthermore, the increased urine output and decreased urine osmolality persisted in CRF rats despite 7 days treatment with 1-desamino-[8-d-arginine]vasopressin (DDAVP, 0.1 μg/h sc) compared with untreated sham-operated controls. Also, there was no change in AQP2 expression (which remained at 38 ± 3% of sham levels, P < 0.05), urine output, or urine osmolality between CRF rats with or without DDAVP treatment. Immunocytochemistry confirmed the decreased AQP2 expression in collecting duct principal cells in CRF rats, with a predominant apical labeling. In conclusion, the results demonstrated that there was a significant vasopressin-resistant downregulation of AQP2 and AQP3 as well as downregulation of AQP1 associated with the polyuria in CRF rats.

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Does aging and off-farm employment hinder farmers’ adoption behavior of soil and water conservation technology in the Loess Plateau?

International Journal of Climate Change Strategies and Management ◽

10.1108/ijccsm-04-2019-0021 ◽

2020 ◽

Vol 12 (1) ◽

pp. 92-107

Author(s):

Xiaohui Huang ◽

Qian Lu ◽

Lili Wang ◽

Maosen Cui ◽

Fei Yang

Keyword(s):

Social Network ◽

Water Conservation ◽

Soil And Water Conservation ◽

Mediating Effect ◽

Content Type ◽

Conservation Technology ◽

Relationship Of ◽

The Impact ◽

The Relationship ◽

Soil And Water

Purpose Based on the survey data of 1,152 households in three provinces of Shaanxi, Gansu and Ningxia on the Loess Plateau, this paper aims to empirically analyze the impact of aging and off-farm employment on farmers’ adoption behavior of soil and water conservation technology. This paper analyzes the moderating effect of social network and the mediating effect of technological cognition in this impact relationship. Design/methodology/approach Based on the above analysis, the second part of this paper is based on relevant theories and constructs a theoretical model of the relationship of aging, off-farm employment, social network, technology cognition and farmers’ adoption behavior of soil and water conservation technology. The third part introduces research methods, variable selection and descriptive statistics analysis of variables. The fourth part, based on the data of Shaanxi, Gansu and Ningxia provinces in the Loess Plateau in 2016, empirically analyzes the impact of aging, off-farm employment and social network on the farmers’ adoption behavior of soil and water conservation technology. This paper further examines the moderating effect of social network and the mediating effect of technology cognition in this influence relationship. Finally, based on the findings of the empirical study, this paper puts forward countermeasures and suggestions. Findings First, aging and off-farm employment have a significant negative impact on farmers’ adoption behavior of soil and water conservation technology, while social network has a significant positive effect. Second, social network has alleviated the effect of aging and off-farm employment on restraining farmers’ adoption behavior of soil and water conservation technology. Third, aging and off-farm employment have restrained farmers’ cognition of soil and water conservation technology. Social network has promoted farmers’ cognition of soil and water conservation technology. Social network plays a moderating role in the impact of aging and off-farm employment on farmers’ cognition of soil and water conservation technology. Technology cognition plays a mediating role in the impact of social network on farmers’ adoption behavior of soil and water conservation technology. Originality/value This paper integrates the aging, off-farm employment and social network into the same analytical framework and reveals their impact on farmers’ adoption behavior of soil and water conservation technology and its action mechanism, which enriches the impact of human capital and social network on farmers’ adoption behavior of soil and water conservation technology. Then taking the social network as a moderator variable, the paper verifies its moderating effect on the relationship of aging, off-farm employment and farmers’ adoption behavior of soil and water conservation technology. Farmers’ technology cognition should be included in the analysis framework to examine the impact of aging, off-farm employment and social network on farmers’ cognition of soil and water conservation technology. Taking the technology cognition as a mediator variable, the paper verifies its mediating effect on the relationship of aging, off-farm employment and farmers’ adoption behavior of soil and water conservation technology.

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Renal phenotype in Bardet-Biedl syndrome: a combined defect of urinary concentration and dilution is associated with defective urinary AQP2 and UMOD excretion

AJP Renal Physiology ◽

10.1152/ajprenal.00224.2016 ◽

2016 ◽

Vol 311 (4) ◽

pp. F686-F694 ◽

Cited By ~ 7

Author(s):

Miriam Zacchia ◽

Enza Zacchia ◽

Enrica Zona ◽

Giovanna Capolongo ◽

Ilaria Raiola ◽

...

Keyword(s):

Collecting Duct ◽

Urine Osmolality ◽

Normal Function ◽

Urinary Concentration ◽

Thick Ascending Limb ◽

Renal Anomalies ◽

Bardet Biedl Syndrome ◽

Urine Albumin ◽

Plasma Factor ◽

Renal Phenotype

The renal phenotype in Bardet-Biedl syndrome (BBS) is highly variable. The present study describes renal findings in 41 BBS patients and analyzes the pathogenesis of hyposthenuria, the most common renal dysfunction. Five of 41 patients (12%) showed an estimated glomerular filtration rate < 60 ml·min−1·1.73 m−2. Urine protein and urine albumin-to-creatinine ratio were over 200 and 30 mg/g in 9/24 and 7/23 patients, respectively. Four of 41 patients showed no renal anomalies on ultrasound. Twenty of 34 patients had hyposthenuria in the absence of renal insufficiency. In all 8 of the hyposthenuric patients studied, dDAVP failed to elevate urine osmolality (Uosm), suggesting a nephrogenic origin. Interestingly, water loading (WL) did not result in a significant reduction of Uosm, indicating combined concentrating and diluting defects. dDAVP infusion induced a significant increase of plasma Factor VIII and von Willebrand Factor levels, supporting normal function of the type 2 vasopressin receptor at least in endothelial cells. While urinary aquaporin 2 (u-AQP2) abundance was not different between patients and controls at baseline, the dDAVP-induced increased u-AQP2 and the WL-induced reduction of u-AQP2 were blunted in patients with a combined concentrating and diluting defect, suggesting a potential role of AQP2 in the defective regulation of water absorption. Urine Uromodulin excretion was reduced in all hyposthenuric patients, suggesting a thick ascending limb defect. Interestingly, renal Na, Cl, Ca, but not K handling was impaired after acute WL but not at basal. In summary, BBS patients show combined urinary concentration and dilution defects; a thick ascending limb and collecting duct tubulopathy may underlie impaired water handling.

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Validation of Surrogates of Urine Osmolality in Population Studies

American Journal of Nephrology ◽

10.1159/000475769 ◽

2017 ◽

Vol 46 (1) ◽

pp. 26-36 ◽

Cited By ~ 5

Author(s):

Sonia Youhanna ◽

Lise Bankir ◽

Paul Jungers ◽

David Porteous ◽

Ozren Polasek ◽

...

Keyword(s):

Metabolic Diseases ◽

Large Population ◽

Urine Osmolality ◽

Population Based ◽

Epidemiologic Studies ◽

Urine Concentration ◽

Total N ◽

Mean Differences ◽

Relationship Of ◽

The Relationship

Background: The importance of vasopressin and/or urine concentration in various kidney, cardiovascular, and metabolic diseases has been emphasized recently. Due to technical constraints, urine osmolality (Uosm), a direct reflect of urinary concentrating activity, is rarely measured in epidemiologic studies. Methods: We analyzed 2 possible surrogates of Uosm in 4 large population-based cohorts (total n = 4,247) and in patients with chronic kidney disease (CKD, n = 146). An estimated Uosm (eUosm) based on the concentrations of sodium, potassium, and urea, and a urine concentrating index (UCI) based on the ratio of creatinine concentrations in urine and plasma were compared to the measured Uosm (mUosm). Results: eUosm is an excellent surrogate of mUosm, with a highly significant linear relationship and values within 5% of mUosm (r = 0.99 or 0.98 in each population cohort). Bland-Altman plots show a good agreement between eUosm and mUosm with mean differences between the 2 variables within ±24 mmol/L. This was verified in men and women, in day and night urine samples, and in CKD patients. The relationship of UCI with mUosm is also significant but is not linear and exhibits more dispersed values. Moreover, the latter index is no longer representative of mUosm in patients with CKD as it declines much more quickly with declining glomerular filtration rate than mUosm. Conclusion: The eUosm is a valid marker of urine concentration in population-based and CKD cohorts. The UCI can provide an estimate of urine concentration when no other measurement is available, but should be used only in subjects with normal renal function.

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Apelin Counteracts Vasopressin-Induced Water Reabsorption via Cross Talk Between Apelin and Vasopressin Receptor Signaling Pathways in the Rat Collecting Duct

Endocrinology ◽

10.1210/en.2014-1257 ◽

2014 ◽

Vol 155 (11) ◽

pp. 4483-4493 ◽

Cited By ~ 28

Author(s):

Annette Hus-Citharel ◽

Laurence Bodineau ◽

Alain Frugière ◽

Fanny Joubert ◽

Nadine Bouby ◽

...

Keyword(s):

Signaling Pathways ◽

Cross Talk ◽

Arginine Vasopressin ◽

Blood Circulation ◽

Direct Action ◽

Collecting Duct ◽

Urine Osmolality ◽

Water Reabsorption ◽

Collecting Ducts ◽

Antagonist Effect

Abstract Apelin receptors (ApelinRs) are expressed along an increasing cortico-medullary gradient in collecting ducts (CDs). We showed here that iv injection of apelin 17 (K17F) in lactating rats characterized by increases in both synthesis and release of arginine vasopressin (AVP) increased diuresis concomitantly with a significant decrease in urine osmolality and no change in Na+ and K+ excretion. Under these conditions, we also observed a significant decrease in apical aquaporin-2 immunolabeling in CD, with a cortico-medullary gradient, suggesting that K17F-induced diuresis could be linked to a direct action of apelin on CD. We then examined the potential cross talk between V1a AVP receptor (V1a-R), V2 AVP receptor (V2-R) and ApelinR signaling pathways in outer medullary CD (OMCD) and inner medullary CD microdissected rat CD. In OMCD, expressing the 3 receptors, K17F inhibited cAMP production and Ca2+ influx induced by 1-desamino-8-D-arginine vasopressin a V2-R agonist. Similar effects were observed in inner medullary CD expressing only V2-R and ApelinR. In contrast, in OMCD, K17F increased by 51% the Ca2+ influx induced by the stimulation of V1a-R by AVP in the presence of the V2-R antagonist SR121463B, possibly enhancing the physiological antagonist effect of V1a-R on V2-R. Thus, the diuretic effect of apelin is not only due to a central effect by inhibiting AVP release in the blood circulation as previously shown but also to a direct action of apelin on CD, by counteracting the antidiuretic effect of AVP occurring via V2-R.

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Decreased vasopressin-mediated renal water reabsorption in rats with chronic aldosterone-receptor blockade

AJP Renal Physiology ◽

10.1152/ajprenal.2000.278.2.f246 ◽

2000 ◽

Vol 278 (2) ◽

pp. F246-F256 ◽

Cited By ~ 30

Author(s):

Thomas E. N. Jonassen ◽

Dominique Promeneur ◽

Sten Christensen ◽

Jørgen S. Petersen ◽

Søren Nielsen

Keyword(s):

Collecting Duct ◽

Water Channel ◽

Urine Osmolality ◽

Urine Flow ◽

Receptor Blockade ◽

Water Reabsorption ◽

Aldosterone Receptor ◽

Duct Ligation ◽

Urine Production ◽

Daily Urine

Previous studies have suggested that mineralocorticoids are needed for a normal action of vasopressin on collecting duct osmotic water permeability. However, the mechanisms behind this are unknown. To investigate if aldosterone-receptor blockade influences vasopressin type 2 receptor (V2)-mediated renal water reabsorption and the renal expression of the vasopressin-regulated water channel aquaporin-2 (AQP2), rats were treated with the aldosterone-receptor antagonist canrenoate (20 mg/day iv) for 4 wk. Daily urine flow was increased significantly by 44%, and urine osmolality was decreased by 27% in canrenoate-treated rats. Acute V2-receptor blockade (OPC-31260, 800 μg ⋅ kg−1 ⋅ h−1) was performed under conditions in which volume depletion was prevented. In control rats, OPC-31260 induced a significant increase in urine flow rate (V, +25%) and free water clearance ([Formula: see text], −29%). In canrenoate-treated rats, the effect of OPC-31260 was significantly reduced, and semiquantiative immunoblotting demonstrated a significant reduction (45%) in AQP2 expression. Because rats with common bile duct ligation (CBL) have a reduced vasopressin-mediated water reabsorption compared with normal rats (V: −24%;[Formula: see text]: −28%, and 86% downregulation of AQP2), the effect of canrenoate combined with OPC-31260 was tested. Canrenoate treatment of CBL rats significantly increased daily urine flow, decreased urine osmolality, and impaired the aquaretic response to OPC-31260 (V: −23%;[Formula: see text]: −31%) with maintained suppression of the renal AQP2 expression. Thus canrenoate treatment of normal and CBL rats showed 1) increased urine production, 2) reduced aquaretic effect of acute V2-receptor blockade, and 3) a marked reduction in AQP2 expression. This strongly supports the view that aldosterone plays a significant role for vasopressin-mediated water reabsorption.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00665.2010 ◽

2011 ◽

Vol 301 (6) ◽

pp. F1303-F1313 ◽

Cited By ~ 13

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.

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