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.

Advances in aquaporin-2 trafficking mechanisms and their implications for treatment of water balance disorders

2020 ◽  
Vol 319 (1) ◽  
pp. C1-C10 ◽  
Author(s):  
Robert A. Fenton ◽  
Sathish K. Murali ◽  
Hanne B. Moeller
Keyword(s):  
Protein Interactions ◽  
Collecting Duct ◽  
Water Channel ◽  
Plasma Osmolality ◽  
Carboxyl Terminus ◽  
Apical Plasma Membrane ◽  
Tail Domain ◽  
Water Reabsorption ◽  
Aquaporin 2

In mammals, conservation of body water is critical for survival and is dependent on the kidneys’ ability to minimize water loss in the urine during periods of water deprivation. The collecting duct water channel aquaporin-2 (AQP2) plays an essential role in this homeostatic response by facilitating water reabsorption along osmotic gradients. The ability to increase the levels of AQP2 in the apical plasma membrane following an increase in plasma osmolality is a rate-limiting step in water reabsorption, a process that is tightly regulated by the antidiuretic hormone arginine vasopressin (AVP). In this review, the focus is on the role of the carboxyl-terminus of AQP2 as a key regulatory point for AQP2 trafficking. We provide an overview of AQP2 structure, disease-causing mutations in the AQP2 carboxyl-terminus, the role of posttranslational modifications such as phosphorylation and ubiquitylation in the tail domain, and their implications for balanced trafficking of AQP2. Finally, we discuss how various modifications of the AQP2 tail facilitate selective protein-protein interactions that modulate the AQP2 trafficking mechanism.

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.

scholarly journals mPGES-1-derived PGE2 mediates dehydration natriuresis

2013 ◽  
Vol 304 (2) ◽  
pp. F214-F221 ◽  
Author(s):  
Zhanjun Jia ◽  
Gang Liu ◽  
Ying Sun ◽  
Yutaka Kakizoe ◽  
Guangju Guan ◽  
...  
Keyword(s):  
Plasma Osmolality ◽  
Renal Medulla ◽  
Fold Increase ◽  
Na Channel ◽  
Prostaglandin E ◽  
Rt Pcr ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Epithelial Na Channel

PGE2 is a natriuretic factor whose production is elevated after water deprivation (WD) but its role in dehydration natriuresis is not well-defined. The goal of the present study was to investigate the role of microsomal prostaglandin E synthase-1 (mPGES-1) in dehydration natriuresis. After 24-h WD, wild-type (WT) mice exhibited a significant increase in 24-h urinary Na+ excretion accompanied with normal plasma Na+ concentration and osmolality. In contrast, WD-induced elevation of urinary Na+ excretion was completely abolished in mPGES-1 knockout (KO) mice in parallel with increased plasma Na+ concentration and a trend increase in plasma osmolality. WD induced a 1.8-fold increase in urinary PGE2 output and a 1.6-fold increase in PGE2 content in the renal medulla of WT mice, both of which were completely abolished by mPGES-1 deletion. Similar patterns of changes were observed for urinary nitrate/nitrite and cGMP. The natriuresis in dehydrated WT mice was associated with a significant downregulation of renal medullary epithelial Na channel-α mRNA and protein, contrasting to unaltered expressions in dehydrated KO mice. By quantitative RT-PCR, WD increased the endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS expressions in the renal medulla of WT mice by 3.9-, 1.48-, and 2.6-fold, respectively, all of which were significantly blocked in mPGES-1 KO mice. The regulation of eNOS expression was further confirmed by immunoblotting. Taken together, our results suggest that mPGES-1-derived PGE2 contributes to dehydration natriuresis likely via NO/cGMP.

scholarly journals Urine concentration in the diabetic mouse requires both urea and water transporters

2013 ◽  
Vol 304 (1) ◽  
pp. F103-F111 ◽  
Author(s):  
Titilayo O. Ilori ◽  
Mitsi A. Blount ◽  
Christopher F. Martin ◽  
Jeff M. Sands ◽  
Janet D. Klein
Keyword(s):  
Collecting Duct ◽  
Urine Osmolality ◽  
Diabetic Mouse ◽  
Urine Concentration ◽  
Diabetic Rat ◽  
Protein Abundance ◽  
Wild Type ◽  
Medullary Collecting Duct ◽  
Additional Stimulation

The regulation of the inner medullary collecting duct (IMCD) urea transporters (UT-A1, UT-A3) and aquaporin-2 (AQP2) and their interactions in diabetic animals is unknown. We investigated whether the urine concentrating defect in diabetic animals was a function of AQP2, the UT-As, or both transporters. UT-A1/UT-A3 knockout (UT-A1/A3 KO) mice produce dilute urine. We gave wild-type (WT) and UT-A1/A3 KO mice vasopressin via minipump for 7 days. In WT mice, vasopressin increased urine osmolality from 3,000 to 4,550 mosmol/kgH2O. In contrast, urine osmolality was low (800 mosmol/kgH2O) in the UT-A1/A3 KOs and remained low following vasopressin. Surprisingly, AQP2 protein abundance increased in UT-A1/A3 KO (114%) and WT (92%) mice. To define the role of UT-A1 and UT-A3 in the diabetic responses, WT and UT-A1/A3 KO mice were injected with streptozotocin (STZ). UT-A1/A3 KO mice showed only 40% survival at 7 days post-STZ injection compared with 70% in WT. AQP2 did not increase in the diabetic UT-A1/A3 KO mice compared with a 133% increase in WT diabetic mice. Biotinylation studies in rat IMCDs showed that membrane accumulation of UT-A1 increased by 68% in response to vasopressin in control rats but was unchanged by vasopressin in diabetic rat IMCDs. We conclude that, even with increased AQP2, UT-A1/UT-A3 is essential to optimal urine concentration. Furthermore, UT-A1 may be maximally membrane associated in diabetic rat inner medulla, making additional stimulation by vasopressin ineffective.

Downregulation of renal vasopressin V2 receptor and aquaporin-2 expression parallels age-associated defects in urine concentration

2004 ◽  
Vol 287 (4) ◽  
pp. F797-F805 ◽  
Author(s):  
Ying Tian ◽  
Ryota Serino ◽  
Joseph G. Verbalis
Keyword(s):  
Collecting Duct ◽  
Water Channel ◽  
Age Groups ◽  
Urine Osmolality ◽  
Brown Norway ◽  
Water Restriction ◽  
Water Excretion ◽  
F1 Hybrid ◽  
Young Rats ◽  
Aquaporin 2

Renal concentrating ability is known to be impaired with aging. The antidiuretic hormone AVP plays an important role in renal water excretion by regulating the membrane insertion and abundance of the water channel aquaporin-2 (AQP2); this effect is primarily mediated via the V2 subtype of the AVP receptor (V2R). This study evaluated the hypothesis that decreased renal sensitivity to AVP, with subsequent altered renal AQP2 expression, contributes to the reduced urinary concentrating ability with aging. Our results show that under baseline conditions, urine osmolality is significantly lower in aged Fischer 344 and Brown-Norway F1 hybrid (F344BN) rats despite equivalent plasma AVP concentrations as in young rats. Levels of kidney V2R mRNA expression and AQP2 abundances were also significantly decreased in aged F344BN rats, as was AQP2 immunostaining in collecting duct cells. In response to moderate water restriction, urine osmolality increased by significantly lesser amounts in aged F344BN rats compared with young rats despite similar increases in plasma AVP levels. Moderate water restriction induced equivalent relative increases in renal AQP2 abundances in all age groups but resulted in significantly lower abundances in total kidney AQP2 protein in aged compared with young F344BN rats. These results therefore demonstrate a functional impairment of renal concentrating ability in aged F344BN rats that is not due to impaired secretion of AVP but rather appears to be related to impaired responsiveness of the kidney to AVP that is secondary, at least in part, to a downregulation of renal V2R expression and AQP2 abundance.

Impairment of osmotically stimulated AVP release in patients with primary polydipsia

1993 ◽  
Vol 265 (6) ◽  
pp. R1247-R1252 ◽  
Author(s):  
A. M. Moses ◽  
B. Clayton
Keyword(s):  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Plasma Osmolality ◽  
Normal Subjects ◽  
Urine Concentration ◽  
Published Data ◽  
Posterior Pituitary ◽  
Primary Polydipsia ◽  
Number Of Factors

The secretion of arginine vasopressin (AVP) from the posterior pituitary is primarily and finely regulated by the osmolality of plasma. Even though a number of factors alter osmolality-induced release of AVP, there are no published data in humans that have addressed the role of chronic overhydration on this phenomenon. To address this problem we have identified eight patients with primary polydipsia using criteria not involving measurement of AVP, and have subjected them to standardized infusions of hypertonic saline. These patients had less AVP in both plasma and urine in relation to plasma osmolality than was found in normal subjects. In addition, their rate of rise of plasma and urine AVP was less than in normal subjects. Their osmotic threshold for AVP release may have been higher than normal. These data demonstrate that chronic overhydration in humans downregulates the release of AVP in response to hypertonicity. This phenomenon may explain the impairment of urine concentration in patients with primary polydipsia and emphasizes the basis of the difficulty that may occur clinically in differentiating between patients with primary polydipsia and partial central diabetes insipidus.

scholarly journals Lixivaptan, a New Generation Diuretic, Counteracts Vasopressin-Induced Aquaporin-2 Trafficking and Function in Renal Collecting Duct Cells

2019 ◽  
Vol 21 (1) ◽  
pp. 183
Author(s):  
Annarita Di Mise ◽  
Maria Venneri ◽  
Marianna Ranieri ◽  
Mariangela Centrone ◽  
Lorenzo Pellegrini ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Water Channel ◽  
Plasma Osmolality ◽  
Kinetic Measurements ◽  
Aquaporin 2 ◽  
Plasma Vasopressin ◽  
Duct Cells ◽  
Collecting Duct Cells ◽  
Renal Collecting Duct ◽  
New Generation

Vasopressin V2 receptor (V2R) antagonists (vaptans) are a new generation of diuretics. Compared with classical diuretics, vaptans promote the excretion of retained body water in disorders in which plasma vasopressin concentrations are inappropriately high for any given plasma osmolality. Under these conditions, an aquaretic drug would be preferable over a conventional diuretic. The clinical efficacy of vaptans is in principle due to impaired vasopressin-regulated water reabsorption via the water channel aquaporin-2 (AQP2). Here, the effect of lixivaptan—a novel selective V2R antagonist—on the vasopressin-cAMP/PKA signaling cascade was investigated in mouse renal collecting duct cells expressing AQP2 (MCD4) and the human V2R. Compared to tolvaptan—a selective V2R antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia—lixivaptan has been predicted to be less likely to cause liver injury. In MCD4 cells, clinically relevant concentrations of lixivaptan (100 nM for 1 h) prevented dDAVP-induced increase of cytosolic cAMP levels and AQP2 phosphorylation at ser-256. Consistent with this finding, real-time fluorescence kinetic measurements demonstrated that lixivaptan prevented dDAVP-induced increase in osmotic water permeability. These data represent the first detailed demonstration of the central role of AQP2 blockade in the aquaretic effect of lixivaptan and suggest that lixivaptan has the potential to become a safe and effective therapy for the treatment of disorders characterized by high plasma vasopressin concentrations and water retention.

scholarly journals The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 265 ◽  
Author(s):  
Sathish Murali ◽  
Takwa Aroankins ◽  
Hanne Moeller ◽  
Robert Fenton
Keyword(s):  
Collecting Duct ◽  
Water Channel ◽  
Mouse Kidney ◽  
Body Water ◽  
Mrna Levels ◽  
E3 Ligases ◽  
Water Homeostasis ◽  
And Function

Aquaporin 2 (AQP2) mediates the osmotic water permeability of the kidney collecting duct in response to arginine vasopressin (VP) and is essential for body water homeostasis. VP effects on AQP2 occur via long-term alterations in AQP2 abundance and short-term changes in AQP2 localization. Several of the effects of VP on AQP2 are dependent on AQP2 phosphorylation and ubiquitylation; post-translational modifications (PTM) that modulate AQP2 subcellular distribution and function. Although several protein kinases, phosphatases, and ubiquitin E3 ligases have been implicated in AQP2 PTM, how AQP2 is deubiquitylated or the role of deubiquitylases (DUBS) in AQP2 function is unknown. Here, we report a novel role of the ubiquitin-specific protease USP4 in modulating AQP2 function. USP4 co-localized with AQP2 in the mouse kidney, and in mpkCCD14 cells USP4 and AQP2 abundance are increased by VP. AQP2 and USP4 co-immunoprecipitated from mpkCCD14 cells and mouse kidney, and in vitro, USP4 can deubiquitylate AQP2. In mpkCCD14 cells, shRNA mediated knockdown of USP4 decreased AQP2 protein abundance, whereas no changes in AQP2 mRNA levels or VP-induced cAMP production were detected. VP-induced AQP2 membrane accumulation in knockdown cells was significantly reduced, which was associated with higher levels of ubiquitylated AQP2. AQP2 protein half-life was also significantly reduced in USP4 knockdown cells. Taken together, the data suggest that USP4 is a key regulator of AQP2 deubiquitylation and that loss of USP4 leads to increased AQP2 ubiquitylation, decreased AQP2 levels, and decreased cell surface AQP2 accumulation upon VP treatment. These studies have implications for understanding body water homeostasis.

Prostaglandin E2 interaction with AVP: effects on AQP2 phosphorylation and distribution

2000 ◽  
Vol 278 (3) ◽  
pp. F388-F394 ◽  
Author(s):  
Marina Zelenina ◽  
Birgitte Mønster Christensen ◽  
Johan Palmér ◽  
Angus C. Nairn ◽  
Søren Nielsen ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Subcellular Distribution ◽  
Collecting Duct ◽  
Water Channel ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Centrifugation Technique ◽  
Renal Inner Medulla ◽  
Intracellular Vesicles ◽  
Dose Dependent

Prostaglandin E2 (PGE2) antagonizes the action of arginine vasopressin (AVP) on collecting duct water permeability. To investigate the mechanism of this antagonism, rat renal inner medulla (IM) was incubated with the two hormones, and the phosphorylation and subcellular distribution of the water channel, aquaporin-2 (AQP2) were studied. Using a phosphorylation state-specific AQP2 antibody, we demonstrated that AVP stimulates AQP2 phosphorylation at the Ser256 protein kinase A consensus site in a time- and dose-dependent manner. In parallel studies using a differential centrifugation technique, we demonstrated that AVP induced translocation of AQP2 from an intracellular vesicle-enriched fraction to a plasma membrane-enriched fraction. PGE2(10− 7 M) added after AVP (10− 8 M) did not decrease AQP2 phosphorylation but reversed AVP-induced translocation of AQP2 to the plasma membrane. Preincubation of IM with PGE2 did not prevent the effects of AVP on AQP2 phosphorylation and trafficking. PGE2 alone did not influence AQP2 phosphorylation and subcellular distribution. Our data indicate that 1) recruitment of AQP2 to the plasma membrane and its retrieval to a pool of intracellular vesicles may be regulated independently, 2) PGE2 may counteract AVP action by activation of AQP2 retrieval, 3) dephosphorylation of AQP2 is not a prerequisite for its internalization.

Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolality

2005 ◽  
Vol 288 (5) ◽  
pp. F912-F920 ◽  
Author(s):  
Yuqiang Ge ◽  
Dowahn Ahn ◽  
Peter K. Stricklett ◽  
Alisa K. Hughes ◽  
Masashi Yanagisawa ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Urine Volume ◽  
Urine Osmolality ◽  
Water Metabolism ◽  
Urinary Osmolality ◽  
Water Load ◽  
Endothelin 1 ◽  
Normal Water

In vitro studies suggest that endothelin-1 (ET-1) inhibits vasopressin (AVP)-stimulated water permeability in the collecting duct (CD). To evaluate the role of CD-derived ET-1 in regulating renal water metabolism, the ET-1 gene was selectively disrupted in the CD (CD ET-1 KO). During normal water intake, urinary osmolality (Uosm), plasma Na concentration, urine volume, and renal aquaporin-2 (AQP2) levels were unchanged, but plasma AVP concentration was reduced in CD ET-1 KO animals. CD ET-1 KO mice had impaired ability to excrete an acute, but not a chronic, water load, and this was associated with increased CD ET-1 mRNA in control, but not CD ET-1 KO, mice. In response to continuous infusion of 1-desamino-8-d-arginine vasopressin, CD ET-1 KO mice had greater increases in Uosm, V2 and AQP2 mRNA, and phosphorylation of AQP2. CD suspensions from CD ET-1 KO mice had enhanced AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ET-1 KO increases renal sensitivity to the urinary concentrating effects of AVP and suggest that ET-1 functions as a physiological autocrine regulator of AVP action in the CD.

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