title: Na+/HCO3-Cotransporter NBCn2 Mediates HCO3-Reclamation in the Apical Membrane of Renal Proximal Tubules.
abstract: The kidney maintains systemic acid-base balance by reclaiming from the renal tubule lumen virtually all HCO3-filtered in glomeruli and by secreting additional H+to titrate luminal buffers. For proximal tubules, which are responsible for about 80% of this activity, it is believed that HCO3-reclamation depends solely on H+secretion, mediated by the apical Na+/H+exchanger NHE3and the vacuolar proton pump. However,NHE3and the proton pump cannot account for all HCO3-reclamation. Here, we investigated the potential contribution of two variants of the electroneutral Na+/HCO3-cotransporter NBCn2, the amino termini of which start with the amino acids MCDL (MCDL-NBCn2) and MEIK (MEIK-NBCn2). Western blot analysis and immunocytochemistry revealed that MEIK-NBCn2 predominantly localizes at the basolateral membrane of medullary thick ascending limbs in the rat kidney, whereas MCDL-NBCn2 localizes at the apical membrane of proximal tubules. Notably, NH4Cl-induced systemic metabolic acidosis or hypokalemic alkalosis downregulated the abundance of MCDL-NBCn2 and reciprocally upregulated NHE3Conversely, NaHCO3-induced metabolic alkalosis upregulated MCDL-NBCn2 and reciprocally downregulated NHE3We propose that the apical membrane of the proximal tubules has two distinct strategies for HCO3-reclamation: the conventional indirect pathway, in which NHE3and the proton pump secrete H+to titrate luminal HCO3-, and the novel direct pathway, in which NBCn2 removes HCO3-from the lumen. The reciprocal regulation of NBCn2 and NHE3under different physiologic conditions is consistent with our mathematical simulations, which suggest that HCO3-uptake and H+secretion have reciprocal efficiencies for HCO3-reclamation versus titration of luminal buffers.
authors.affiliation: Department of Biophysics and Molecular Physiology, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology School of Life Science and Technology, Wuhan, Hubei, China; and.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Guo
authors.affiliation: Department of Biophysics and Molecular Physiology, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology School of Life Science and Technology, Wuhan, Hubei, China; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biophysics and Molecular Physiology, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology School of Life Science and Technology, Wuhan, Hubei, China; and.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Biophysics and Molecular Physiology, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology School of Life Science and Technology, Wuhan, Hubei, China; and.
authors.forename: Jin-Lin
authors.initials: JL
authors.lastname: Wang
authors.affiliation: Department of Biophysics and Molecular Physiology, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology School of Life Science and Technology, Wuhan, Hubei, China; and.
authors.forename: Zhang-Dong
authors.initials: ZD
authors.lastname: Xie
authors.affiliation: Department of Biophysics and Molecular Physiology, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology School of Life Science and Technology, Wuhan, Hubei, China; and.
authors.forename: Kang-Jing
authors.initials: KJ
authors.lastname: Chen
authors.affiliation: Department of Biophysics and Molecular Physiology, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology School of Life Science and Technology, Wuhan, Hubei, China; and.|Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Deng-Ke
authors.initials: DK
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Rossana
authors.initials: R
authors.lastname: Occhipinti
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Walter F
authors.initials: WF
authors.lastname: Boron
authors.affiliation: Department of Biophysics and Molecular Physiology, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology School of Life Science and Technology, Wuhan, Hubei, China; and liming.chen@hust.edu.cn.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Chen
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D017136:Ion Transport; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D027982:Sodium-Bicarbonate Symporters / Q000502:physiology*
chemical_list: D001639:Bicarbonates; D027982:Sodium-Bicarbonate Symporters
keywords: acid-base balance; acidosis; bicarbonate reabsorption; mathematical simulation; metabolic; metabolic alkalosis; proximal tubule