{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:32:50Z","timestamp":1792114370539,"version":"4.4.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2017,8]]},"abstract":"\n The kidney maintains systemic acid-base balance by reclaiming from the renal tubule lumen virtually all HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n filtered in glomeruli and by secreting additional H\n +<\/jats:sup>\n to titrate luminal buffers. For proximal tubules, which are responsible for about 80% of this activity, it is believed that HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n reclamation depends solely on H\n +<\/jats:sup>\n secretion, mediated by the apical Na\n +<\/jats:sup>\n \/H\n +<\/jats:sup>\n exchanger NHE\n 3<\/jats:sub>\n and the vacuolar proton pump. However,\n NHE3<\/jats:sub>\n and the proton pump cannot account for all HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n reclamation. Here, we investigated the potential contribution of two variants of the electroneutral Na\n +<\/jats:sup>\n \/HCO\n 3<\/jats:sub>\n \u2013<\/jats:sup>\n 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, NH\n 4<\/jats:sub>\n Cl-induced systemic metabolic acidosis or hypokalemic alkalosis downregulated the abundance of MCDL-NBCn2 and reciprocally upregulated NHE\n 3<\/jats:sub>\n . Conversely, NaHCO\n 3<\/jats:sub>\n -induced metabolic alkalosis upregulated MCDL-NBCn2 and reciprocally downregulated NHE\n 3<\/jats:sub>\n . We propose that the apical membrane of the proximal tubules has two distinct strategies for HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n reclamation: the conventional indirect pathway, in which NHE\n 3<\/jats:sub>\n and the proton pump secrete H\n +<\/jats:sup>\n to titrate luminal HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n , and the novel direct pathway, in which NBCn2 removes HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n from the lumen. The reciprocal regulation of NBCn2 and NHE\n 3<\/jats:sub>\n under different physiologic conditions is consistent with our mathematical simulations, which suggest that HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n uptake and H\n +<\/jats:sup>\n secretion have reciprocal efficiencies for HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n reclamation versus titration of luminal buffers.\n <\/jats:p>","DOI":"10.1681\/asn.2016080930","type":"journal-article","created":{"date-parts":[[2017,3,9]],"date-time":"2017-03-09T20:25:29Z","timestamp":1489091129000},"page":"2409-2419","source":"Crossref","is-referenced-by-count":36,"title":["Na+\/HCO3 \u2013 Cotransporter NBCn2 Mediates HCO3 \u2212 Reclamation in the Apical Membrane of Renal Proximal Tubules"],"prefix":"10.1681","volume":"28","author":[{"given":"Yi-Min","family":"Guo","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Liu","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhang-Dong","family":"Xie","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang-Jing","family":"Chen","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deng-Ke","family":"Wang","sequence":"additional","affiliation":[{"name":"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"},{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossana","family":"Occhipinti","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter F.","family":"Boron","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Ming","family":"Chen","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,3,9]]},"reference":[{"key":"B1-20230819","first-page":"F647","article-title":"Mechanisms of active H+ secretion in the proximal tubule.","volume":"245","author":"Aronson","year":"1983","journal-title":"Am J Physiol"},{"key":"B2-20230819","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1146\/annurev.physiol.61.1.699","article-title":"Electrogenic Na+\/HCO3 - cotransporters: Cloning and physiology.","volume":"61","author":"Romero","year":"1999","journal-title":"Annu Rev Physiol"},{"key":"B3-20230819","doi-asserted-by":"crossref","first-page":"F864","DOI":"10.1152\/classicessays.00005.2004","article-title":"Two classic papers in acid-base physiology: Contributions of R. F. Pitts, R. S. Alexander, and W. D. Lotspeich.","volume":"287","author":"Giebisch","year":"2004","journal-title":"Am J Physiol Renal Physiol"},{"key":"B4-20230819","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1002\/cphy.c140021","article-title":"Molecular mechanisms and regulation of urinary acidification.","volume":"4","author":"Kurtz","year":"2014","journal-title":"Compr Physiol"},{"key":"B5-20230819","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1085\/jgp.81.1.53","article-title":"Intracellular pH regulation in the renal proximal tubule of the salamander. Basolateral HCO3- transport.","volume":"81","author":"Boron","year":"1983","journal-title":"J Gen Physiol"},{"key":"B6-20230819","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/387409a0","article-title":"Expression cloning and characterization of a renal electrogenic Na+\/HCO3 - cotransporter.","volume":"387","author":"Romero","year":"1997","journal-title":"Nature"},{"key":"B7-20230819","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1152\/physrev.00023.2012","article-title":"The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters.","volume":"93","author":"Parker","year":"2013","journal-title":"Physiol Rev"},{"key":"B8-20230819","doi-asserted-by":"crossref","first-page":"F1117","DOI":"10.1152\/ajprenal.2001.281.6.F1117","article-title":"Role of NHE isoforms in mediating bicarbonate reabsorption along the nephron.","volume":"281","author":"Wang","year":"2001","journal-title":"Am J Physiol Renal Physiol"},{"key":"B9-20230819","doi-asserted-by":"crossref","first-page":"F789","DOI":"10.1152\/ajprenal.00033.2004","article-title":"Inhibition of bicarbonate reabsorption in the rat proximal tubule by activation of luminal P2Y1 receptors.","volume":"287","author":"Bailey","year":"2004","journal-title":"Am J Physiol Renal Physiol"},{"key":"B10-20230819","first-page":"F298","article-title":"Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice.","volume":"277","author":"Wang","year":"1999","journal-title":"Am J Physiol"},{"key":"B11-20230819","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/969","article-title":"Renal and intestinal absorptive defects in mice lacking the NHE3 Na+\/H+ exchanger.","volume":"19","author":"Schultheis","year":"1998","journal-title":"Nat Genet"},{"key":"B12-20230819","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1007\/s00109-013-1015-3","article-title":"Proximal tubule specific knockout of the Na+\/H+ exchanger NHE3: Effects on bicarbonate absorption and ammonium excretion.","volume":"91","author":"Li","year":"2013","journal-title":"J Mol Med (Berl)"},{"key":"B13-20230819","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.mam.2012.10.008","article-title":"The SLC4 family of bicarbonate (HCO3 \u2212) transporters.","volume":"34","author":"Romero","year":"2013","journal-title":"Mol Aspects Med"},{"key":"B14-20230819","doi-asserted-by":"crossref","first-page":"e55974","DOI":"10.1371\/journal.pone.0055974","article-title":"Cloning and functional characterization of novel variants and tissue-specific expression of alternative amino and carboxyl termini of products of slc4a10.","volume":"8","author":"Liu","year":"2013","journal-title":"PLoS One"},{"key":"B15-20230819","doi-asserted-by":"crossref","first-page":"12241","DOI":"10.1038\/srep12241","article-title":"Effects of Nt-truncation and coexpression of isolated Nt domains on the membrane trafficking of electroneutral Na+\/HCO3 - cotransporters.","volume":"5","author":"Wang","year":"2015","journal-title":"Sci Rep"},{"key":"B16-20230819","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.neuroscience.2007.10.015","article-title":"Use of a new polyclonal antibody to study the distribution and glycosylation of the sodium-coupled bicarbonate transporter NCBE in rodent brain.","volume":"151","author":"Chen","year":"2008","journal-title":"Neuroscience"},{"key":"B17-20230819","doi-asserted-by":"crossref","first-page":"F531","DOI":"10.1152\/ajprenal.2001.281.3.F531","article-title":"Immunocytochemical localization of Na-K-ATPase alpha- and gamma-subunits in rat kidney.","volume":"281","author":"Wetzel","year":"2001","journal-title":"Am J Physiol Renal Physiol"},{"key":"B18-20230819","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1038\/ki.1995.404","article-title":"Expression of NHE-3 in the apical membrane of rat renal proximal tubule and thick ascending limb.","volume":"48","author":"Amemiya","year":"1995","journal-title":"Kidney Int"},{"key":"B19-20230819","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1016\/j.bbagen.2013.12.002","article-title":"Renal aquaporins and water balance disorders.","volume":"1840","author":"Kortenoeven","year":"2014","journal-title":"Biochim Biophys Acta"},{"key":"B20-20230819","doi-asserted-by":"crossref","first-page":"10932","DOI":"10.1016\/S0021-9258(18)38060-8","article-title":"Fine specificity mapping and topography of an isozyme-specific epitope of the Na,K-ATPase catalytic subunit.","volume":"263","author":"Felsenfeld","year":"1988","journal-title":"J Biol Chem"},{"key":"B21-20230819","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1046\/j.1523-1755.2001.00995.x","article-title":"Coordinated down-regulation of NBC-1 and NHE-3 in sodium and bicarbonate loading.","volume":"60","author":"Amlal","year":"2001","journal-title":"Kidney Int"},{"key":"B22-20230819","doi-asserted-by":"crossref","first-page":"32749","DOI":"10.1074\/jbc.271.51.32749","article-title":"Role of NHE3 in mediating renal brush border Na+-H+ exchange. Adaptation to metabolic acidosis.","volume":"271","author":"Wu","year":"1996","journal-title":"J Biol Chem"},{"key":"B23-20230819","doi-asserted-by":"crossref","first-page":"F341","DOI":"10.1152\/ajprenal.00104.2001","article-title":"Chronic metabolic acidosis upregulates rat kidney Na-HCO cotransporters NBCn1 and NBC3 but not NBC1.","volume":"282","author":"Kwon","year":"2002","journal-title":"Am J Physiol Renal Physiol"},{"key":"B24-20230819","doi-asserted-by":"crossref","first-page":"F903","DOI":"10.1152\/ajprenal.00437.2002","article-title":"NBCn1 is a basolateral Na+-HCO3 - cotransporter in rat kidney inner medullary collecting ducts.","volume":"286","author":"Praetorius","year":"2004","journal-title":"Am J Physiol Renal Physiol"},{"key":"B25-20230819","first-page":"F917","article-title":"Chronic metabolic acidosis increases NHE3 protein abundance in rat kidney.","volume":"271","author":"Amb\u00fchl","year":"1996","journal-title":"Am J Physiol"},{"key":"B26-20230819","doi-asserted-by":"crossref","first-page":"F835","DOI":"10.1152\/ajprenal.00188.2001","article-title":"Rat proximal NHE3 adapts to chronic acid-base disorders but not to chronic changes in dietary NaCl intake.","volume":"282","author":"Eladari","year":"2002","journal-title":"Am J Physiol Renal Physiol"},{"key":"B27-20230819","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.semnephrol.2013.04.006","article-title":"Acid-base and potassium homeostasis.","volume":"33","author":"Lee Hamm","year":"2013","journal-title":"Semin Nephrol"},{"key":"B28-20230819","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.2215\/CJN.07400715","article-title":"Acid-Base Homeostasis.","volume":"10","author":"Hamm","year":"2015","journal-title":"Clin J Am Soc Nephrol"},{"key":"B29-20230819","doi-asserted-by":"crossref","first-page":"F1376","DOI":"10.1152\/ajprenal.00186.2002","article-title":"Altered expression of renal NHE3, TSC, BSC-1, and ENaC subunits in potassium-depleted rats.","volume":"283","author":"Elkjaer","year":"2002","journal-title":"Am J Physiol Renal Physiol"},{"key":"B30-20230819","doi-asserted-by":"crossref","first-page":"F1244","DOI":"10.1152\/ajprenal.00176.2003","article-title":"Altered expression of renal acid-base transporters in rats with lithium-induced NDI.","volume":"285","author":"Kim","year":"2003","journal-title":"Am J Physiol Renal Physiol"},{"key":"B31-20230819","first-page":"58P","article-title":"The effect of inhibitors of anion exchange and chloride conductance on fluid reabsorption from rat renal proximal convoluted tubule.","volume":"361","author":"Green","year":"1985","journal-title":"J Physiol"},{"key":"B32-20230819","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1113\/expphysiol.1988.sp003229","article-title":"The effect of DIDS on fluid reabsorption from the proximal convoluted tubule of the rat: Dependence on the presence of bicarbonate.","volume":"73","author":"White","year":"1988","journal-title":"Q J Exp Physiol"},{"key":"B33-20230819","first-page":"F417","article-title":"Intracellular pH in the isolated perfused rabbit proximal straight tubule.","volume":"249","author":"Sasaki","year":"1985","journal-title":"Am J Physiol"},{"key":"B34-20230819","doi-asserted-by":"crossref","first-page":"C841","DOI":"10.1152\/ajpcell.00049.2014","article-title":"Evidence from mathematical modeling that carbonic anhydrase II and IV enhance CO2 fluxes across Xenopus oocyte plasma membranes.","volume":"307","author":"Occhipinti","year":"2014","journal-title":"Am J Physiol Cell Physiol"},{"key":"B35-20230819","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.jtbi.2012.06.016","article-title":"A reaction-diffusion model of CO2 influx into an oocyte.","volume":"309","author":"Somersalo","year":"2012","journal-title":"J Theor Biol"},{"key":"B36-20230819","doi-asserted-by":"crossref","first-page":"C220","DOI":"10.1152\/ajpcell.1981.241.5.C220","article-title":"Interaction of NH4 + and Li+ with the renal microvillus membrane Na+-H+ exchanger.","volume":"241","author":"Kinsella","year":"1981","journal-title":"Am J Physiol"},{"key":"B37-20230819","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.neuroscience.2010.06.005","article-title":"Distribution of NBCn2 (SLC4A10) splice variants in mouse brain.","volume":"169","author":"Liu","year":"2010","journal-title":"Neuroscience"},{"key":"B38-20230819","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1046\/j.1523-1755.1998.00901.x","article-title":"Regulation of renal phosphate transport by acute and chronic metabolic acidosis in the rat.","volume":"53","author":"Amb\u00fchl","year":"1998","journal-title":"Kidney Int"},{"key":"B39-20230819","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1042\/bj1420575","article-title":"A rapid method for the preparation of microvilli from rabbit kidney.","volume":"142","author":"Booth","year":"1974","journal-title":"Biochem J"},{"key":"B40-20230819","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1152\/physrev.00024.2001","article-title":"Aquaporins in the kidney: From molecules to medicine.","volume":"82","author":"Nielsen","year":"2002","journal-title":"Physiol Rev"}],"container-title":["Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/00001751-201708000-00017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:28:51Z","timestamp":1786130931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/00001751-201708000-00017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,9]]},"references-count":40,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1681\/asn.2016080930","relation":{},"ISSN":["1046-6673","1533-3450"],"issn-type":[{"value":"1046-6673","type":"print"},{"value":"1533-3450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,9]]}}}