High salt differentially regulates surface NKCC2 expression in thick ascending limbs of Dahl salt-sensitive and salt-resistant rats

Am J Physiol Renal Physiol. 2011 May;300(5):F1096-104. doi: 10.1152/ajprenal.00600.2010. Epub 2011 Feb 9.


NaCl reabsorption by the thick ascending limb of the loop of Henle (THAL) occurs via the apical Na-K-2Cl cotransporter, NKCC2. Overall, NKCC2 activity and NaCl reabsorption are regulated by the amount of NKCC2 at the apical surface, and also by phosphorylation. Dahl salt-sensitive rats (SS) exhibit higher NaCl reabsorption by the THAL compared with Dahl salt-resistant rats (SR), and they become hypertensive during high-salt (HS) intake. However, the effect of HS on THAL transport, surface NKCC2 expression, and NKCC2 NH(2)-terminus phosphorylation has not been studied. We hypothesized that HS enhances surface NKCC2 and its phosphorylation in THALs from Dahl SS. THAL suspensions were obtained from a group of SS and SR rats on normal-salt (NS) or HS intake. In SR rats THAL NaCl transport measured as furosemide-sensitive oxygen consumption was decreased by HS (-34%, P < 0.05). In contrast, HS did not affect THAL transport in SS rats. As expected, HS increased systolic blood pressure only in SS rats (Δ 23 ± 2 mmHg, P < 0.002) but not in SR rats (Δ 5 ± 3 mmHg). We next tested the effect of HS intake on apical surface NKCC2 and its NH(2)-terminus threonine phosphorylation (P-NKCC2) in SS and SR rats. HS intake decreased surface NKCC2 by 15 ± 2% (P < 0.03) in THALs from SR without affecting total NKCC2 or NH(2)-terminus P-NKCC2. In contrast, in SS rats HS intake increased surface NKCC2 by 54 ± 6% (P < 0.01) without affecting total NKCC2 expression or P-NKCC2. We conclude that HS intake causes different effects on surface NKCC2 in SS and SR rats. Our data suggest that enhanced surface NKCC2 in SS rats might contribute to enhanced NaCl reabsorption in SS rats during HS intake.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption
  • Animals
  • Blood Pressure
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Disease Models, Animal
  • Furosemide / pharmacology
  • Hypertension / etiology
  • Hypertension / metabolism*
  • Loop of Henle / drug effects
  • Loop of Henle / metabolism*
  • Male
  • Oxygen Consumption
  • Phosphorylation
  • Rats
  • Rats, Inbred Dahl
  • Sodium Chloride, Dietary / metabolism*
  • Sodium Potassium Chloride Symporter Inhibitors / pharmacology
  • Sodium-Potassium-Chloride Symporters / drug effects
  • Sodium-Potassium-Chloride Symporters / metabolism*
  • Solute Carrier Family 12, Member 1
  • Threonine
  • Time Factors


  • Slc12a1 protein, rat
  • Sodium Chloride, Dietary
  • Sodium Potassium Chloride Symporter Inhibitors
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 1
  • Threonine
  • Furosemide