Altered expression of renal acid-base transporters in rats with lithium-induced NDI.
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.
Kim
Young-Hee
YH
The Water and Salt Research Center, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus C, Denmark.
Kwon
Tae-Hwan
TH
Christensen
Birgitte M
BM
Nielsen
Jakob
J
Wall
Susan M
SM
Madsen
Kirsten M
KM
Frøkiaer
Jørgen
J
Nielsen
Søren
S
D000138:Acidosis / Q000378:metabolism*; D000143:Acids / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000276:immunology / Q000378:metabolism*; D000918:Antibody Specificity; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D008094:Lithium; D008297:Male; D026901:Membrane Transport Proteins; D006180:Proton-Translocating ATPases / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027982:Sodium-Bicarbonate Symporters / Q000276:immunology / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000276:immunology / Q000378:metabolism*; D000076988:Sulfate Transporters; D014556:Urine
D000143:Acids; D001457:Anion Exchange Protein 1, Erythrocyte; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; C422004:Slc4a4 protein, rat; D027982:Sodium-Bicarbonate Symporters; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; D008094:Lithium; D006180:Proton-Translocating ATPases