title: Renal tubular NHE3 is required in the maintenance of water and sodium chloride homeostasis.
abstract: The sodium/proton exchanger isoform 3 (NHE3) is expressed in the intestine and the kidney, where it facilitates sodium (re)absorption and proton secretion. The importance of NHE3 in the kidney for sodium chloride homeostasis, relative to the intestine, is unknown. Constitutive tubule-specific NHE3 knockout mice (NHE3loxloxCre)did not show significant differences compared to control mice in body weight, blood pH or bicarbonate and plasma sodium, potassium, or aldosterone levels. Fluid intake, urinary flow rate, urinary sodium/creatinine, and pH were significantly elevated in NHE3loxloxCremice, while urine osmolality and GFR were significantly lower. Water deprivation revealed a small urinary concentrating defect in NHE3loxloxCremice on a control diet, exaggerated on low sodium chloride. Ten days of low or high sodium chloride diet did not affect plasma sodium in control mice; however, NHE3loxloxCremice were susceptible to low sodium chloride (about -4 mM) or high sodium chloride intake (about +2 mM) versus baseline, effects without differences in plasma aldosterone between groups. Blood pressure was significantly lower in NHE3loxloxCremice and was sodium chloride sensitive. In control mice, the expression of the sodium/phosphate co-transporter Npt2c was sodium chloride sensitive. However, lack of tubular NHE3 blunted Npt2c expression. Alterations in the abundances of sodium/chloride cotransporter and its phosphorylation at threonine 58 as well as the abundances of the α-subunit of the epithelial sodium channel, and its cleaved form, were also apparent in NHE3loxloxCremice. Thus, renal NHE3 is required to maintain blood pressure and steady-state plasma sodium levels when dietary sodium chloride intake is modified.
authors.affiliation: InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenton
authors.affiliation: InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark; VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: Søren B
authors.initials: SB
authors.lastname: Poulsen
authors.affiliation: VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: de la Mora Chavez
authors.affiliation: Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA; Research Services, Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
authors.forename: Manoocher
authors.initials: M
authors.lastname: Soleimani
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Dominguez Rieg
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA. Electronic address: trieg@health.usf.edu.
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
mesh_terms: D000818:Animals; D001794:Blood Pressure; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006339:Heart Rate; D006706:Homeostasis; D007684:Kidney Tubules / Q000378:metabolism*; D018345:Mice, Knockout; D049992:Sodium Chloride Symporters / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3 / Q000378:metabolism*
chemical_list: D053503:Epithelial Sodium Channels; C000613386:Slc9a3 protein, mouse; D049992:Sodium Chloride Symporters; D017673:Sodium Chloride, Dietary; D000074083:Sodium-Hydrogen Exchanger 3
keywords: aldosterone; distal tubule; hypernatremia; hyponatremia; proximal tubule