The electrogenic Na+-HCO3– cotransporter NBCe1 encoded by SLC4A4 gene plays essential roles in the regulation of intracellular/extracellular pH. Three NBCe1 variants are thought to mediate distinct physiological role...The electrogenic Na+-HCO3– cotransporter NBCe1 encoded by SLC4A4 gene plays essential roles in the regulation of intracellular/extracellular pH. Three NBCe1 variants are thought to mediate distinct physiological roles with different modes of transport stoichiometry. Homozygous inactivating mutations in NBCe1 cause the isolated proximal renal tubular acidosis (pRTA) invariably associated with ocular abnormalities. Functional analyses indicate that more than 50% reduction in NBCe1 activity may be required to induce severe acidemia. Some of the pRTA- related NBCe1 mutations, which show defective me-mbrane expression in mammalian cells, are also associated with migraine. Dysregulation of local pH in brain due to the loss of NBCe1 activity in astrocytes may underlie this association. Two types of NBCe1 deficient animals, NBCe1 knockout and W516X knockin mice, have been reported. Both of them show severe acidemia and early lethality unless they are treated with alkali. In isolated renal proximal tubules from W516X knockin mice, both NBCe1 activity and the rate of bicarbonate absorption are severely reduced, confirming the essential role of NBCe1 in bicarbonate absorption from this nephron segment. In this review, we summarize the recent data about physiological and pathophysiological roles of NBCe1 in health and diseases.展开更多
The kidney plays quite an important role in the regulation of acid-base homeostasis. The dysfunction of renal acid-base regulation causes diseases such as developmental disorder, bone malformation, calcification of ey...The kidney plays quite an important role in the regulation of acid-base homeostasis. The dysfunction of renal acid-base regulation causes diseases such as developmental disorder, bone malformation, calcification of eye and brain, etc. In the kidney, this regulation is performed, to a considerable part, in the proximal tubule of the nephron. In the luminal side the key player is sodium-proton exchanger type 3 (NHE3), whereas sodium-bicarbonate cotransporter (NBCe1) plays the critical role in the basolateral side. In the cytoplasm there is carbonic anhydrase type 2 (CAII) that intermediates the conversion of CO2/ . Interestingly, in human, mutations have been found in NBCe1 and CAII but not in NHE3 so far. Mutations of NBCe1 lead to severe proximal renal tubular acidosis (pRTA) and other systemic manifestations. In animal model studies, however, the relative contribution of NHE3 to proximal tubule functions remains controversial. Recently, V-ATPase with renal specific subunits is suggested to have some roles in the regulation of proximal tubule functions. In this review, we will discuss the regulation of acid-base transport in the proximal tubule and the updates.展开更多
文摘The electrogenic Na+-HCO3– cotransporter NBCe1 encoded by SLC4A4 gene plays essential roles in the regulation of intracellular/extracellular pH. Three NBCe1 variants are thought to mediate distinct physiological roles with different modes of transport stoichiometry. Homozygous inactivating mutations in NBCe1 cause the isolated proximal renal tubular acidosis (pRTA) invariably associated with ocular abnormalities. Functional analyses indicate that more than 50% reduction in NBCe1 activity may be required to induce severe acidemia. Some of the pRTA- related NBCe1 mutations, which show defective me-mbrane expression in mammalian cells, are also associated with migraine. Dysregulation of local pH in brain due to the loss of NBCe1 activity in astrocytes may underlie this association. Two types of NBCe1 deficient animals, NBCe1 knockout and W516X knockin mice, have been reported. Both of them show severe acidemia and early lethality unless they are treated with alkali. In isolated renal proximal tubules from W516X knockin mice, both NBCe1 activity and the rate of bicarbonate absorption are severely reduced, confirming the essential role of NBCe1 in bicarbonate absorption from this nephron segment. In this review, we summarize the recent data about physiological and pathophysiological roles of NBCe1 in health and diseases.
文摘The kidney plays quite an important role in the regulation of acid-base homeostasis. The dysfunction of renal acid-base regulation causes diseases such as developmental disorder, bone malformation, calcification of eye and brain, etc. In the kidney, this regulation is performed, to a considerable part, in the proximal tubule of the nephron. In the luminal side the key player is sodium-proton exchanger type 3 (NHE3), whereas sodium-bicarbonate cotransporter (NBCe1) plays the critical role in the basolateral side. In the cytoplasm there is carbonic anhydrase type 2 (CAII) that intermediates the conversion of CO2/ . Interestingly, in human, mutations have been found in NBCe1 and CAII but not in NHE3 so far. Mutations of NBCe1 lead to severe proximal renal tubular acidosis (pRTA) and other systemic manifestations. In animal model studies, however, the relative contribution of NHE3 to proximal tubule functions remains controversial. Recently, V-ATPase with renal specific subunits is suggested to have some roles in the regulation of proximal tubule functions. In this review, we will discuss the regulation of acid-base transport in the proximal tubule and the updates.
