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      Abnormal increase in urinary aquaporin-2 excretion in response to hypertonic saline in essential hypertension

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          Abstract

          Background

          Dysregulation of the expression/shuttling of the aquaporin-2 water channel (AQP2) and the epithelial sodium channel (ENaC) in renal collecting duct principal cells has been found in animal models of hypertension. We tested whether a similar dysregulation exists in essential hypertension.

          Methods

          We measured urinary excretion of AQP2 and ENaC β-subunit corrected for creatinine (u-AQP2 CR, u-ENaC β-CR), prostaglandin E2 (u-PGE 2) and cyclic AMP (u-cAMP), fractional sodium excretion (FE Na), free water clearance (C H2O), as well as plasma concentrations of vasopressin (AVP), renin (PRC), angiotensin II (Ang II), aldosterone (Aldo), and atrial and brain natriuretic peptide (ANP, BNP) in 21 patients with essential hypertension and 20 normotensive controls during 24-h urine collection (baseline), and after hypertonic saline infusion on a 4-day high sodium (HS) diet (300 mmol sodium/day) and a 4-day low sodium (LS) diet (30 mmol sodium/day).

          Results

          At baseline, no differences in u-AQP2 CR or u-ENaC β-CR were measured between patients and controls. U-AQP2 CR increased significantly more after saline in patients than controls, whereas u-ENaC β-CR increased similarly. The saline caused exaggerated natriuretic increases in patients during HS intake. Neither baseline levels of u-PGE 2, u-cAMP, AVP, PRC, Ang II, Aldo, ANP, and BNP nor changes after saline could explain the abnormal u-AQP2 CR response.

          Conclusions

          No differences were found in u-AQP2 CR and u-ENaC β-CR between patients and controls at baseline. However, in response to saline, u-AQP2 CR was abnormally increased in patients, whereas the u-ENaC β-CR response was normal. The mechanism behind the abnormal AQP2 regulation is not clarified, but it does not seem to be AVP-dependent.

          Clinicaltrial.gov identifier

          NCT00345124.

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          Most cited references38

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          Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.

          The amiloride-sensitive epithelial sodium channel constitutes the rate-limiting step for sodium reabsorption in epithelial cells that line the distal part of the renal tubule, the distal colon, the duct of several exocrine glands, and the lung. The activity of this channel is upregulated by vasopressin and aldosterone, hormones involved in the maintenance of sodium balance, blood volume and blood pressure. We have identified the primary structure of the alpha-subunit of the rat epithelial sodium channel by expression cloning in Xenopus laevis oocytes. An identical subunit has recently been reported. Here we identify two other subunits (beta and gamma) by functional complementation of the alpha-subunit of the rat epithelial Na+ channel. The ion-selective permeability, the gating properties and the pharmacological profile of the channel formed by coexpressing the three subunits in oocytes are similar to that of the native channel.
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            Liddle's syndrome: Heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel

            Liddle's syndrome (pseudoaldosteronism) is an autosomal dominant form of human hypertension characterized by a constellation of findings suggesting constitutive activation of the amiloride-sensitive distal renal epithelial sodium channel. We demonstrate complete linkage of the gene encoding the beta subunit of the epithelial sodium channel to Liddle's syndrome in Liddle's original kindred. Analysis of this gene reveals a premature stop codon that truncates the cytoplasmic carboxyl terminus of the encoded protein in affected subjects. Analysis of subjects with Liddle's syndrome from four additional kindreds demonstrates either premature termination or frameshift mutations in this same carboxy-terminal domain in all four. These findings demonstrate that Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel and have implications for the regulation of this epithelial ion channel as well as blood pressure homeostasis.
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              Urinary excretion of aquaporin-2 in patients with diabetes insipidus.

              Urine-concentrating ability is regulated by vasopressin. Recently, the specific water-channel protein of the renal collecting duct, known as aquaporin-2, was cloned. However, it is not certain whether this molecule is responsive to vasopressin. We measured the urinary excretion of aquaporin-2 and its response to vasopressin in 11 normal subjects and 9 patients with central or nephrogenic diabetes insipidus. The urine samples were collected during periods of dehydration and hydration and after the administration of vasopressin. Urine samples were analyzed for aquaporin-2 by the Western blot assay and immunogold labeling, and the amount of aquaporin-2 was determined by radioimmunoassay. Aquaporin-2 was detectable in the urine in both soluble and membrane-bound forms. In the five normal subjects tested, the mean (+/- SE) urinary excretion of aquaporin-2 was 11.2 +/- 2.2 pmol per milligram of creatinine after a period of dehydration, and it decreased to 3.9 +/- 1.9 pmol per milligram of creatinine (P = 0.03) during the second hour after a period of hydration. In the six other normal subjects, an infusion of desmopressin (1-desamino-8-D-arginine vasopressin) increased the urinary excretion of aquaporin-2 from 0.8 +/- 0.3 to 11.2 +/- 1.6 pmol per milligram of creatinine (P < 0.001). The five patients with central diabetes insipidus also had increases in urinary excretion of aquaporin-2 in response to the administration of vasopressin, but the four patients with X-linked or non-X-linked nephrogenic diabetes insipidus did not. Aquaporin-2 is detectable in the urine, and changes in the urinary excretion of this protein can be used as an index of the action of vasopressin on the kidney.
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                Author and article information

                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central
                1471-2369
                2012
                27 March 2012
                : 13
                : 15
                Affiliations
                [1 ]Department of Medical Research, Holstebro Hospital, Laegaardvej 12, 7500 Holstebro, Denmark
                [2 ]Department of Medicine, Holstebro Hospital, Holstebro, Denmark
                [3 ]University of Aarhus, Aarhus, Denmark
                Article
                1471-2369-13-15
                10.1186/1471-2369-13-15
                3386017
                22452789
                a437a9a4-2d62-4c5b-900c-07bc4b1ec6b3
                Copyright ©2012 Graffe et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 September 2011
                : 27 March 2012
                Categories
                Research Article

                Nephrology
                Nephrology

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