Local pH domains regulate NHE3-mediated Na⁺ reabsorption in the renal proximal tubule

TY - JOUR

T1 - Local pH domains regulate NHE3-mediated Na⁺ reabsorption in the renal proximal tubule

AU - Brasen, Jens Christian

AU - Burford, James L

AU - McDonough, Alicia A

AU - von Holstein-Rathlou, Niels-Henrik

AU - Peti-Peterdi, Janos

N1 - Copyright © 2014 the American Physiological Society.

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

KW - Animals

KW - Blood Pressure

KW - Carbonic Anhydrases

KW - Cytosol

KW - Hydrogen-Ion Concentration

KW - Hypertension, Renal

KW - Kidney Tubules, Proximal

KW - Male

KW - Microvilli

KW - Rats

KW - Rats, Sprague-Dawley

KW - Sodium

KW - Sodium-Hydrogen Antiporter

KW - Sodium-Potassium-Exchanging ATPase

U2 - 10.1152/ajprenal.00174.2014

DO - 10.1152/ajprenal.00174.2014

M3 - Journal article

C2 - 25298526

SN - 1931-857X

VL - 307

SP - F1249-62

JO - American Journal of Physiology: Renal Physiology

JF - American Journal of Physiology: Renal Physiology

IS - 11

ER -