Effect of metabolic acidosis on neonatal proximal tubule acidification.
The serum bicarbonate in neonates is lower than adults due in large part to a lower rate of proximal tubule acidification. It is unclear if the neonatal proximal tubule is functioning at maximal capacity or if the proximal tubule can respond to metabolic acidosis as has been described in adult proximal tubules. We find that neonatal mouse brush-border membranes have a lower Na(+)/H(+) exchanger (NHE) 3 protein abundance (neonate 0.11 ± 0.05 vs. adult 0.64 ± 0.07; P < 0.05) and a higher NHE8 protein abundance (neonate 1.0 ± 0.01 vs. adult 0.13 ± 0.09; P < 0.001) compared with adults. To examine if neonates can adapt to acidosis, neonatal mice were gavaged with either acid or vehicle for 4 days, resulting in a drop in serum bicarbonate from 19.5 ± 1.0 to 8.9 ± 0.6 meq/l (P < 0.001). Proximal convoluted tubule Na(+)/H(+) exchanger activity (dpH(i)/dt) was 1.68 ± 0.19 pH units/min in control tubules and 2.49 ± 0.60 pH units/min in acidemic neonatal mice (P < 0.05), indicating that the neonatal proximal tubule can respond to metabolic acidosis with an increase in Na(+)/H(+) exchanger activity. Similarly, brush-border membrane vesicles from neonatal rats had an increase in Na(+)/H(+) exchanger activity with acidemia that was almost totally inhibited by 10(-6) M 5-(N-ethyl-n-isopropyl)-amiloride, a dose that has little effect on NHE3 but inhibits NHE8. There was a significant increase in both NHE3 (vehicle 0.35 ± 0.07 vs. acid 0.73 ± 0.07; P < 0.003) and NHE8 brush-border membrane protein abundance (vehicle 0.41 ± 0.05 vs. acid 0.73 ± 0.06; P < 0.001) in acidemic mouse neonates compared with controls. A comparable increase in NHE3 and NHE8 was found in neonatal rats with acidosis. In conclusion, the neonatal proximal tubule can adapt to metabolic acidosis with an increase in Na(+)/H(+) exchanger activity.
Twombley
Katherine
K
Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9063, USA.
Gattineni
Jyothsna
J
Bobulescu
Ion Alexandru
IA
Dwarakanath
Vangipuram
V
Baum
Michel
M
D000138:Acidosis / Q000235:genetics / Q000378:metabolism*; D000222:Adaptation, Physiological; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001639:Bicarbonates / Q000097:blood; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006863:Hydrogen-Ion Concentration; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008871:Microvilli / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D001639:Bicarbonates; D012333:RNA, Messenger; C000613386:Slc9a3 protein, mouse; C000613387:Slc9a3 protein, rat; C471945:Slc9a8 protein, mouse; C502388:Slc9a8 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; C039614:ethylisopropylamiloride