TY - JOUR
T1 - Deficient acid handling with distal RTA in the NBCe2 knockout mouse
AU - Wen, Donghai
AU - Yuan, Yang
AU - Cornelius, Ryan J.
AU - Li, Huaqing
AU - Warner, Paige C.
AU - Wang, Bangchen
AU - Wang-France, Jun
AU - Boettger, Thomas
AU - Sansom, Steven C.
N1 - Publisher Copyright:
© 2015 the American Physiological Society.
PY - 2015/9/15
Y1 - 2015/9/15
N2 - In many circumstances, the pathogenesis of distal renal tubular acidosis (dRTA) is not understood. In the present study, we report that a mouse model lacking the electrogenic Na+-HCO3- cotransporter [NBCe2/Slc4a5; NBCe2 knockout (KO) mice] developed dRTA after an oral acid challenge. NBCe2 expression was identified in the connecting tubule (CNT) of wild-type mice, and its expression was significantly increased after acid loading. NBCe2 KO mice did not have dRTA when on a standard mouse diet. However, after acid loading, NBCe2 KO mice exhibited complete features of dRTA, characterized by insufficient urinary acidification, hyperchloremic hypokalemic metabolic acidosis, and hypercalciuria. Additional experiments showed that NBCe2 KO mice had decreased luminal transepithelial potential in the CNT, as revealed by micropuncture. Further immunofluorescence and Western blot experiments found that NBCe2 KO mice had increased expression of H+-ATPase B1 in the plasma membrane. These results showed that NBCe2 KO mice with acid loading developed increased urinary K+ and Ca2+ wasting due to decreased luminal transepithelial potential in the CNT. NBCe2 KO mice compensated to maintain systemic pH by increasing H+-ATPase in the plasma membrane. Therefore, defects in NBCe2 can cause dRTA, and NBCe2 has an important role to regulate urinary acidification and the transport of K+ and Ca2+ in the distal nephron.
AB - In many circumstances, the pathogenesis of distal renal tubular acidosis (dRTA) is not understood. In the present study, we report that a mouse model lacking the electrogenic Na+-HCO3- cotransporter [NBCe2/Slc4a5; NBCe2 knockout (KO) mice] developed dRTA after an oral acid challenge. NBCe2 expression was identified in the connecting tubule (CNT) of wild-type mice, and its expression was significantly increased after acid loading. NBCe2 KO mice did not have dRTA when on a standard mouse diet. However, after acid loading, NBCe2 KO mice exhibited complete features of dRTA, characterized by insufficient urinary acidification, hyperchloremic hypokalemic metabolic acidosis, and hypercalciuria. Additional experiments showed that NBCe2 KO mice had decreased luminal transepithelial potential in the CNT, as revealed by micropuncture. Further immunofluorescence and Western blot experiments found that NBCe2 KO mice had increased expression of H+-ATPase B1 in the plasma membrane. These results showed that NBCe2 KO mice with acid loading developed increased urinary K+ and Ca2+ wasting due to decreased luminal transepithelial potential in the CNT. NBCe2 KO mice compensated to maintain systemic pH by increasing H+-ATPase in the plasma membrane. Therefore, defects in NBCe2 can cause dRTA, and NBCe2 has an important role to regulate urinary acidification and the transport of K+ and Ca2+ in the distal nephron.
KW - Connecting tubule
KW - Distal renal tubular acidosis
KW - Electrogenic Na-HCO cotransporter
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UR - http://www.scopus.com/inward/citedby.url?scp=84941651909&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00163.2015
DO - 10.1152/ajprenal.00163.2015
M3 - Article
C2 - 26109087
AN - SCOPUS:84941651909
SN - 1931-857X
VL - 309
SP - F523-F530
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 6
ER -