NHE2-mediated bicarbonate reabsorption in the distal tubule of NHE3 null mice

J Physiol. 2004 Dec 15;561(Pt 3):765-75. doi: 10.1113/jphysiol.2004.074716. Epub 2004 Oct 7.


NHE3(-/-) mice display a profound defect in proximal tubule bicarbonate reabsorption but are only mildly acidotic owing to reduced glomerular filtration rate and enhanced H(+) secretion in distal nephron segments. In vivo microperfusion of rat distal tubules suggests that a significant fraction of bicarbonate reabsorption in this nephron segment is mediated by NHE2. Two approaches were used to evaluate the role of distal tubule NHE2 in compensating for the proximal defect of H(+) secretion in NHE3(-/-) mice. First, renal clearance experiments were used to assess the impact of HOE694, an inhibitor with significant affinity for NHE2, on excretion of bicarbonate in NHE3(-/-) and NHE2(-/-) mice. Second, in vivo micropuncture and microperfusion were employed to measure the concentration of bicarbonate in early distal tubule fluid and to measure distal bicarbonate reabsorption during a constant bicarbonate load. Our data show that HOE694 had no effect on urinary bicarbonate excretion in NHE3(+/+) mice, whereas bicarbonate excretion was higher in NHE3(-/-) mice receiving HOE694. HOE694 induced a significant increase in bicarbonate excretion in mice given an acute bicarbonate load, but there was no effect during metabolic acidosis. Bicarbonate excretion was not affected by HOE694 in bicarbonate-loaded NHE2(-/-) mice. In vivo micropuncture revealed that early distal bicarbonate concentration was elevated in both bicarbonate-loaded and NHE3(-/-) mice. Further, microperfusion experiments showed that HOE694-sensitive bicarbonate reabsorption capacity was higher in acidotic and NHE3 null animals. We conclude that NHE2 contributes importantly to acidification in the distal tubule, and that it plays a major role in limiting urinary bicarbonate losses in states in which a high luminal bicarbonate load is presented to the distal tubule, such as in NHE3 null mice.

Publication types

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

MeSH terms

  • Acidosis / metabolism
  • Animals
  • Bicarbonates / metabolism*
  • Blood Pressure / drug effects
  • Glomerular Filtration Rate / drug effects
  • Guanidines / pharmacology
  • Kidney Tubules, Distal / drug effects
  • Kidney Tubules, Distal / metabolism*
  • Mice
  • Mice, Knockout
  • Potassium / metabolism
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / antagonists & inhibitors
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / physiology*
  • Sulfones / pharmacology


  • Bicarbonates
  • Guanidines
  • Slc9a2 protein, mouse
  • Slc9a2 protein, rat
  • Slc9a3 protein, mouse
  • Slc9a3 protein, rat
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Sulfones
  • 3-methylsulfonyl-4-piperidinobenzoyl guanidine
  • Potassium