title: Local pH domains regulate NHE3-mediated Na⁺ reabsorption in the renal proximal tubule.
abstract: The proximal tubule Na(+)/H(+) exchanger 3 (NHE3), located in the apical dense microvilli (brush border), plays a major role in the reabsorption of NaCl and water in the renal proximal tubule. In response to a rise in blood pressure NHE3 redistributes in the plane of the plasma membrane to the base of the brush border, where NHE3 activity is reduced. This NHE3 redistribution is assumed to provoke pressure natriuresis; however, it is unclear how NHE3 redistribution per se reduces NHE3 activity. To investigate if the distribution of NHE3 in the brush border can change the reabsorption rate, we constructed a spatiotemporal mathematical model of NHE3-mediated Na(+) reabsorption across a proximal tubule cell and compared the model results with in vivo experiments in rats. The model predicts that when NHE3 is localized exclusively at the base of the brush border, it creates local pH microdomains that reduce NHE3 activity by >30%. We tested the model's prediction experimentally: the rat kidney cortex was loaded with the pH-sensitive fluorescent dye BCECF, and cells of the proximal tubule were imaged in vivo using confocal fluorescence microscopy before and after an increase of blood pressure by ∼50 mmHg. The experimental results supported the model by demonstrating that a rise of blood pressure induces the development of pH microdomains near the bottom of the brush border. These local changes in pH reduce NHE3 activity, which may explain the pressure natriuresis response to NHE3 redistribution.
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Biomedical Engineering, Department of Electrical Engineering, Technical University of Denmark, Lyngby, Denmark; and jcbrasen@sund.ku.dk.
authors.forename: Jens Christian
authors.initials: JC
authors.lastname: Brasen
authors.affiliation: Departments of Physiology and Biophysics and Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California; and.
authors.forename: James L
authors.initials: JL
authors.lastname: Burford
authors.affiliation: Department of Cell and Neurobiology, University of Southern California, Los Angeles, California.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: McDonough
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Niels-Henrik
authors.initials: NH
authors.lastname: Holstein-Rathlou
authors.affiliation: Departments of Physiology and Biophysics and Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California; and.
authors.forename: Janos
authors.initials: J
authors.lastname: Peti-Peterdi
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002256:Carbonic Anhydrases / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006977:Hypertension, Renal / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D008871:Microvilli / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D012964:Sodium; D002256:Carbonic Anhydrases; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Na+/H+ exchanger 3; intravital confocal microscopy; pressure natriuresis; proximal tubule; spatiotemporal mathematical model