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1 Institute of Physiology and2 The Water and Salt Research Center, University of Aarhus, Denmark
The electroneutral Na+-dependent HCO3- transporter NBCn1 is strongly expressed in the basolateral membrane of rat medullary thick ascending limb cells (mTAL) and is up-regulated during NH4+-induced metabolic acidosis. Here we used in vitro perfusion and BCECF video-imaging of mTAL tubules to investigate functional localization and regulation of Na+-dependent HCO3- influx during NH4+-induced metabolic acidosis. Tubule acidification was induced by removing luminal Na+ (
pHi: 0.88 ± 0.11 pH units, n= 10). Subsequently the basolateral perfusion solution was changed to CO2/HCO3- buffer with and without Na+. Basolateral Na+–H+ exchange function was inhibited with amiloride. Na+-dependent HCO3- influx was determined by calculating initial base flux of Na+-mediated re-alkalinization. In untreated animals base flux was 8.4 ± 0.9 pmol min-1 mm-1. A 2.4-fold increase of base flux to 21.8 ± 3.2 pmol min-1 mm-1 was measured in NH4+-treated animals (11 days, n= 11). Na+-dependent re-alkalinization was significantly larger when compared to control animals (0.38 ± 0.03 versus 0.22 ± 0.02 pH units, n= 10). In addition, Na+-dependent HCO3- influx was of similar magnitude in chloride-free medium and also up-regulated after NH4+ loading. Na+-dependent HCO3- influx was not inhibited by 400 µM DIDS. A strong up-regulation of NBCn1 staining was confirmed in immunolabelling experiments. RT-PCR analysis revealed no evidence for the Na+-dependent HCO3- transporter NBC4 or the two Na+-dependent CI-/HCO3- exchangers NCBE and NDCBE. These data strongly indicate that rat mTAL tubules functionally express basolateral DIDS-insensitive NBCn1. Function and protein are strongly up-regulated during NH4+-induced metabolic acidosis. We suggest that NBCn1-mediated basolateral HCO3- influx is important for basolateral NH3 exit and thus NH4+ excretion by means of setting pHi to a more alkaline value.
(Received 6 May 2003;
accepted after revision 10 December 2003;
first published online 12 December 2003)
Corresponding author J. Leipziger: Ole Worms Allé 160, 8000 Aarhus C, Denmark. Email: leip{at}fi.au.dk
These authors contributed equally to this work. This article has been cited by other articles:
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