Molecular physiology of urinary concentrating mechanism: regulation of aquaporin water channels by vasopressin

1997 ◽  
Vol 272 (1) ◽  
pp. F3-F12 ◽  
Author(s):  
M. A. Knepper
Keyword(s):  
Collecting Duct ◽  
Water Channel ◽  
Renal Medulla ◽  
Water Channels ◽  
Renal Physiology ◽  
Molecular Physiology ◽  
Water Excretion ◽  
Aquaporin 2 ◽  
New Research

The purpose of this review is to illustrate the application of molecular methodologies to the investigation of a fundamentally integrative problem in renal physiology, namely, the mechanism of regulation of water excretion by the kidney and the concomitant concentration of solutes in the urine. A new revolution in renal physiology is occurring as new research tools have become available as a result of the cloning of cDNAs for many of the major transporters and receptors in the renal medulla. Among the important renal medullary transporters are the aquaporin water channels, which mediate the osmotic water transport across renal medullary epithelia. One of these water channels, aquaporin-2, has been shown to be the target for short-term regulation of collecting duct water permeability by vasopressin. In addition, two collecting duct water channels, aquaporin-2 and aquaporin-3, are targets for long-term regulation by vasopressin through effects on the absolute expression levels of the water channel proteins. This review focuses on the mechanisms of both short- and long-term regulation of these water channels by vasopressin.

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.

Long-term regulation of urinary concentrating capacity

1998 ◽  
Vol 275 (3) ◽  
pp. F332-F333 ◽  
Author(s):  
Mark A. Knepper
Keyword(s):  
Water Retention ◽  
Collecting Duct ◽  
Hormone Secretion ◽  
Water Channel ◽  
Absolute Abundance ◽  
Inappropriate Antidiuretic Hormone Secretion ◽  
Aquaporin 2 ◽  
Collecting Duct Cells ◽  
Antidiuretic Action

Urinary concentrating capacity is regulated in part by a long-term adaptational process involving changes in the absolute abundance of the aquaporin-2 water channel in collecting duct cells. Alterations in aquaporin-2 abundance play key roles in the pathophysiology of several water balance disorders. Escape from the antidiuretic action of vasopressin, e.g. in the syndrome of inappropriate antidiuretic hormone secretion, involves a selective downregulation of aquaporin-2 expression. Excessive water retention causing hyponatremia in volume-expanded states such as congestive heart failure appears to be due in part to a failure of this escape mechanism.

scholarly journals Lessons on Renal Physiology from Transgenic Mice Lacking Aquaporin Water Channels

1999 ◽  
Vol 10 (5) ◽  
pp. 1126-1135
Author(s):  
A. S. VERKMAN
Keyword(s):  
Proximal Tubule ◽  
Knockout Mice ◽  
Collecting Duct ◽  
Water Channel ◽  
Water Channels ◽  
Renal Physiology ◽  
Vasa Recta ◽  
Phenotype Analysis ◽  
Type Water

Abstract. Several aquaporin-type water channels are expressed in kidney: AQP1 in the proximal tubule, thin descending limb of Henle, and vasa recta; AQP2, AQP3, and AQP4 in the collecting duct; AQP6 in the papilla; and AQP7 in the proximal tubule. AQP2 is the vasopressin-regulated water channel that is important in hereditary and acquired diseases affecting urine-concentrating ability. It has been difficult to establish the roles of the other aquaporins in renal physiology because suitable aquaporin inhibitors are not available. One approach to the problem has been to generate and analyze transgenic knockout mice in which individual aquaporins have been selectively deleted by targeted gene disruption. Phenotype analysis of kidney and extrarenal function in knockout mice has been very informative in defining the role of aquaporins in organ physiology and addressing basic questions regarding the route of transepithelial water transport and the mechanism of near isoosmolar fluid reabsorption. This article describes new renal physiologic insights revealed by phenotype analysis of aquaporin-knockout mice and the prospects for further basic and clinical developments.

scholarly journals Expression of VAMP-2-like protein in kidney collecting duct intracellular vesicles. Colocalization with Aquaporin-2 water channels.

1995 ◽  
Vol 96 (4) ◽  
pp. 1834-1844 ◽  
Author(s):  
S Nielsen ◽  
D Marples ◽  
H Birn ◽  
M Mohtashami ◽  
N O Dalby ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Water Channels ◽  
Kidney Collecting Duct ◽  
Aquaporin 2 ◽  
Intracellular Vesicles

scholarly journals α-Actinin 4 Links Vasopressin Short-Term and Long-Term Regulation of Aquaporin-2 in Kidney Collecting Duct Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Cheng-Hsuan Ho ◽  
Hsiu-Hui Yang ◽  
Shih-Han Su ◽  
Ai-Hsin Yeh ◽  
Ming-Jiun Yu
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Nuclear Translocation ◽  
Collecting Duct ◽  
Apical Plasma Membrane ◽  
Membrane Insertion ◽  
Short Term ◽  
Aquaporin 2 ◽  
Mrna And Protein Expression

Water permeability of the kidney collecting ducts is regulated by the peptide hormone vasopressin. Between minutes and hours (short-term), vasopressin induces trafficking of the water channel protein aquaporin-2 to the apical plasma membrane of the collecting duct principal cells to increase water permeability. Between hours and days (long-term), vasopressin induces aquaporin-2 gene expression. Here, we investigated the mechanisms that bridge the short-term and long-term vasopressin-mediated aquaporin-2 regulation by α-actinin 4, an F-actin crosslinking protein and a transcription co-activator of the glucocorticoid receptor. Vasopressin induced F-actin depolymerization and α-actinin 4 nuclear translocation in the mpkCCD collecting duct cell model. Co-immunoprecipitation followed by immunoblotting showed increased interaction between α-actinin 4 and glucocorticoid receptor in response to vasopressin. ChIP-PCR showed results consistent with α-actinin 4 and glucocorticoid receptor binding to the aquaporin-2 promoter. α-actinin 4 knockdown reduced vasopressin-induced increases in aquaporin-2 mRNA and protein expression. α-actinin 4 knockdown did not affect vasopressin-induced glucocorticoid receptor nuclear translocation, suggesting independent mechanisms of vasopressin-induced nuclear translocation of α-actinin 4 and glucocorticoid receptor. Glucocorticoid receptor knockdown profoundly reduced vasopressin-induced increases in aquaporin-2 mRNA and protein expression. In the absence of glucocorticoid analog dexamethasone, vasopressin-induced increases in glucocorticoid receptor nuclear translocation and aquaporin-2 mRNA were greatly reduced. α-actinin 4 knockdown further reduced vasopressin-induced increase in aquaporin-2 mRNA in the absence of dexamethasone. We conclude that glucocorticoid receptor plays a major role in vasopressin-induced aquaporin-2 gene expression that can be enhanced by α-actinin 4. In the absence of vasopressin, α-actinin 4 crosslinks F-actin underneath the apical plasma membrane, impeding aquaporin-2 membrane insertion. Vasopressin-induced F-actin depolymerization in one hand facilitates aquaporin-2 apical membrane insertion and in the other hand frees α-actinin 4 to enter the nucleus where it binds glucocorticoid receptor to enhance aquaporin-2 gene expression.

Abstract 9411: Urine Aquaporin-2 Level is a Novel Marker for the Better Prognosis After Long-Term Tolvaptan Treatment in Patients With Advanced Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Teruhiko Imamura ◽  
Koichiro Kinugawa ◽  
Takeo Fujino ◽  
Toshiro Inaba ◽  
Hisataka Maki ◽  
...  
Keyword(s):  
Heart Failure ◽  
De Novo ◽  
Collecting Duct ◽  
Initial Response ◽  
Aquaporin 2 ◽  
Long Term Treatment ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Introduction: Preserved function of collecting duct is essential for the response to tolvaptan (TLV), and urinary level of aquaporin 2 (U-AQP2) can be a marker for vasopressin-dependent activity of collecting duct. Hypothesis: Higher levels of U-AQP2 in proportion to plasma levels of vasopressin (P-AVP) may be associated with better initial responses to TLV and eventually result in the improved prognosis after long-term treatment of TLV. Methods: Consecutive 60 in-hospital patients with stage D heart failure (HF) who received TLV on a de novo basis were enrolled during 2011-2013. We also selected 60 HF patients by propensity score matching who were hospitalized during the same period but never treated with TLV. Events were defined as death and/or HF re-hospitalization. Results: TLV (3.75-15 mg/day) was continuously administered except death or ventricular assist device implantation occurred. There were 41 patients (group 1) who had increases in UV over the first 24 h after TLV initiation, and all of them had U-AQP2/P-AVP ≥0.5 х103 with higher U-AQP2 levels (5.42 ± 3.54 ng/mL) before TLV treatment. On the other hand, UV rather decreased even after TLV initiation in 19 patients over the first 24 h (group 2). Those in the group 2 universally had U-AQP2/P-AVP <0.5 х103, extremely low U-AQP2 levels (0.76 ± 0.59 ng/mL, p<0.001 vs. group 1), and similar P-AVP with the group 1 at baseline. The 41 and 19 patients without TLV treatment (group 3 and 4) were respectively matched to the group 1 and 2 by propensity scores. Interestingly, every patient in the group 3 had U-AQP2/P-AVP ≥0.5 х103, and vice versa in the group 4. Among the four groups, congestion-related symptoms were only improved in the group 1 after 1 month of enrollment. The patients in the group 1 had significantly better event-free survival over 2-year by TLV treatment compared with the group 3 (76% vs. 43%, p<0.014). In contrast, the patients in the group 2 and 4 had very poor prognoses regardless of TLV treatment (7% vs. 11%, p=0.823). Conclusions: U-AQP2/P-AVP is a novel predictor for the initial response to TLV in HF patients. Patients with higher U-AQP2/P-AVP may enjoy a better prognosis by long-term TLV treatment probably due to efficient resolution of congestion.

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.

Assignment of the human gene for the water channel of renal collecting duct Aquaporin 2 (AQP2) to chromosome 12 region q12→q13

1994 ◽  
Vol 66 (4) ◽  
pp. 260-262 ◽  
Author(s):  
P.M. Deen ◽  
D.O. Weghuis ◽  
R.J. Sinke ◽  
Geurts van Kessel ◽  
B. Wieringa ◽  
...  
Keyword(s):  
Human Gene ◽  
Collecting Duct ◽  
Water Channel ◽  
Chromosome 12 ◽  
Aquaporin 2 ◽  
Renal Collecting Duct

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.

scholarly journals A Role for VAMP8/Endobrevin in Surface Deployment of the Water Channel Aquaporin 2

2009 ◽  
Vol 30 (1) ◽  
pp. 333-343 ◽  
Author(s):  
Cheng-Chun Wang ◽  
Chee Peng Ng ◽  
Hong Shi ◽  
Hwee Chien Liew ◽  
Ke Guo ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Protein ◽  
Collecting Duct ◽  
Water Channel ◽  
Snare Proteins ◽  
Snare Protein ◽  
Aquaporin 2 ◽  
Duct Cells ◽  
Collecting Duct Cells ◽  
Intracellular Vesicles

ABSTRACT Vesicle-associated-membrane protein 8 (VAMP8) is highly expressed in the kidney, but the exact physiological and molecular functions executed by this v-SNARE protein in nephrons remain elusive. Here, we show that the depletion of VAMP8 in mice resulted in hydronephrosis. Furthermore, the level of the vasopressin-responsive water channel aquaporin 2 (AQP2) was increased by three- to fivefold in VAMP8-null mice. Forskolin and [desamino-Cys1, D-Arg8]-vasopressin (DDAVP)-induced AQP2 exocytosis was impaired in VAMP8-null collecting duct cells. VAMP8 was revealed to colocalize with AQP2 on intracellular vesicles and to interact with the plasma membrane t-SNARE proteins syntaxin4 and syntaxin3, suggesting that VAMP8 mediates the regulated fusion of AQP2-positive vesicles with the plasma membrane.

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