Altered expression of renal acid-base transporters in rats with lithium-induced NDI

Am J Physiol Renal Physiol. 2003 Dec;285(6):F1244-57. doi: 10.1152/ajprenal.00176.2003. Epub 2003 Aug 26.


Prolonged lithium treatment of humans and rodents often results in hyperchloremic metabolic acidosis. This is thought to be caused by diminished net H+ secretion and/or excessive back-diffusion of acid equivalents. To explore whether lithium treatment is associated with changes in the expression of key renal acid-base transporters, semiquantitative immunoblotting and immunocytochemistry were performed using kidneys from lithium-treated (n = 6) and control (n = 6) rats. Rats treated with lithium for 28 days showed decreased urine pH, whereas no significant differences in blood pH and plasma HCO3- levels were observed. Immunoblot analysis revealed that lithium treatment induced a significant increase in the expression of the H+-ATPase (B1-subunit) in cortex (190 +/- 18%) and inner stripe of the outer medulla (190 +/- 9%), and a dramatic increase in inner medulla (900 +/- 104%) in parallel to an increase in the expression of type 1 anion exchanger (400 +/- 40%). This was confirmed by immunocytochemistry and immunoelectron microscopy, which also revealed increased density of intercalated cells. Moreover, immunoblotting and immunocytochemistry revealed a significant increase in the expression of the type 1 electrogenic Na+-HCO3- cotransporter (NBC) in cortex (200 +/- 23%) and of the electroneutral NBCn1 in inner stripe of the outer medulla (250 +/- 54%). In contrast, there were no changes in the expression of Na+/H+ exchanger-3 or of the Cl-/HCO3- exchanger pendrin. These results demonstrate that the expression of specific renal acid-base transporters is markedly altered in response to long-term lithium treatment. This is likely to represent direct or compensatory effects to increase the capacity for HCO3- reabsorption, NH4+ reabsorption, and proton secretion to prevent the development of systemic metabolic acidosis.

Publication types

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

MeSH terms

  • Acidosis / metabolism*
  • Acids / pharmacokinetics
  • Acids / urine
  • Animals
  • Anion Exchange Protein 1, Erythrocyte / immunology
  • Anion Exchange Protein 1, Erythrocyte / metabolism*
  • Antibody Specificity
  • Blotting, Western
  • Carrier Proteins / metabolism
  • Diabetes Insipidus, Nephrogenic / chemically induced
  • Diabetes Insipidus, Nephrogenic / metabolism*
  • Hydrogen-Ion Concentration
  • Immunohistochemistry
  • Kidney Cortex / metabolism
  • Kidney Tubules, Collecting / metabolism
  • Lithium
  • Male
  • Membrane Transport Proteins*
  • Proton-Translocating ATPases / immunology
  • Proton-Translocating ATPases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Bicarbonate Symporters / immunology
  • Sodium-Bicarbonate Symporters / metabolism
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / immunology
  • Sodium-Hydrogen Exchangers / metabolism*
  • Sulfate Transporters
  • Urine


  • Acids
  • Anion Exchange Protein 1, Erythrocyte
  • Carrier Proteins
  • Membrane Transport Proteins
  • SLC26A4 protein, human
  • Slc4a4 protein, rat
  • Sodium-Bicarbonate Symporters
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Sulfate Transporters
  • Lithium
  • Proton-Translocating ATPases