{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T21:31:26Z","timestamp":1786483886002,"version":"build-2736575974"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","funder":[{"DOI":"10.13039\/501100004836","name":"Independent Research Fund Denmark","doi-asserted-by":"publisher","award":["4004-00137B"],"award-info":[{"award-number":["4004-00137B"]}],"id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004836","name":"Independent Research Fund Denmark","doi-asserted-by":"publisher","award":["10-094816"],"award-info":[{"award-number":["10-094816"]}],"id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2021,4]]},"abstract":"\n Significance Statement<\/jats:title>\n \n Recovery from metabolic acidosis necessitates increased renal net acid excretion through urinary elimination of NH\n 4<\/jats:sub>\n +<\/jats:sup>\n . Renal thick ascending limbs (TALs) contribute to a medullary shortcut, where NH\n 4<\/jats:sub>\n +<\/jats:sup>\n originating from proximal tubules is ultimately secreted in collecting ducts. NH\n 4<\/jats:sub>\n +<\/jats:sup>\n transfer across TALs requires a basolateral exit pathway for H\n +<\/jats:sup>\n to avoid intracellular accumulation. Experiments with knockout mice show that the Na\n +<\/jats:sup>\n \/HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n cotransporter NBCn1 mediates basolateral HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n uptake and increases NH\n 4<\/jats:sub>\n +<\/jats:sup>\n reabsorption in TAL, amplifies the corticomedullary NH\n 4<\/jats:sub>\n +<\/jats:sup>\n gradient, elevates the capacity for urinary NH\n 4<\/jats:sub>\n +<\/jats:sup>\n excretion, and accelerates recovery of arterial blood pH and [HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n ] during metabolic acidosis. NBCn1 is crucial for acid-base handling in TALs, and for early renal compensation of systemic acid-base disturbances.\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n The electroneutral Na\n +<\/jats:sup>\n \/HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n cotransporter NBCn1 (Slc4a7) is expressed in basolateral membranes of renal medullary thick ascending limbs (mTALs). However, direct evidence that NBCn1 contributes to acid-base handling in mTALs, urinary net acid excretion, and systemic acid-base homeostasis has been lacking.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Metabolic acidosis was induced in wild-type and NBCn1 knockout mice. Fluorescence-based intracellular pH recordings were performed and NH\n 4<\/jats:sub>\n +<\/jats:sup>\n transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH\n 4<\/jats:sub>\n +<\/jats:sup>\n ] was measured in renal biopsies, NH\n 4<\/jats:sub>\n +<\/jats:sup>\n excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Basolateral Na\n +<\/jats:sup>\n \/HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na\n +<\/jats:sup>\n \/HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n cotransport activity increased four-fold in mTALs from wild-type mice, but remained unchanged in mTALs from NBCn1 knockout mice. Correspondingly, NBCn1 protein expression in wild-type mice increased ten-fold in the inner stripe of renal outer medulla during metabolic acidosis. During systemic acid loading, knockout of NBCn1 inhibited the net NH\n 4<\/jats:sub>\n +<\/jats:sup>\n reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH\n 4<\/jats:sub>\n +<\/jats:sup>\n gradient, reduced the capacity for urinary NH\n 4<\/jats:sub>\n +<\/jats:sup>\n excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n ] from their initial decline.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n During metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n uptake and transepithelial NH\n 4<\/jats:sub>\n +<\/jats:sup>\n reabsorption in mTALs, renal medullary NH\n 4<\/jats:sub>\n +<\/jats:sup>\n accumulation, urinary NH\n 4<\/jats:sub>\n +<\/jats:sup>\n excretion, and early recovery of arterial blood pH and standard [HCO\n 3<\/jats:sub>\n \u2212<\/jats:sup>\n ]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H\n +<\/jats:sup>\n released during NH\n 4<\/jats:sub>\n +<\/jats:sup>\n reabsorption across mTALs.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2019060613","type":"journal-article","created":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T14:12:48Z","timestamp":1610028768000},"page":"852-865","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":19,"title":["NBCn1 Increases NH4 + Reabsorption Across Thick Ascending Limbs, the Capacity for Urinary NH4 + Excretion, and Early Recovery from Metabolic Acidosis"],"prefix":"10.1681","volume":"32","author":[{"given":"Jeppe S. M.","family":"Olsen","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Svendsen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peder","family":"Berg","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vibeke S.","family":"Dam","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6398-1035","authenticated-orcid":false,"given":"Mads V.","family":"Sorensen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir V.","family":"Matchkov","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Leipziger","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"},{"name":"Aarhus Institute of Advanced Studies, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5078-9279","authenticated-orcid":false,"given":"Ebbe","family":"Boedtkjer","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,1,7]]},"reference":[{"key":"B1-20240826","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1046\/j.1525-139x.2000.00062.x","article-title":"Influence of diet on acid-base balance","volume":"13","author":"Remer","year":"2000","journal-title":"Semin Dial"},{"key":"B2-20240826","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/cphy.c120010","article-title":"Renal ammonia metabolism and transport","volume":"3","author":"Weiner","year":"2013","journal-title":"Compr Physiol"},{"key":"B3-20240826","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1146\/annurev.ph.56.030194.003203","article-title":"Ammonium transport by the thick ascending limb of Henle\u2019s loop","volume":"56","author":"Good","year":"1994","journal-title":"Annu Rev Physiol"},{"key":"B4-20240826","doi-asserted-by":"crossref","first-page":"F1","DOI":"10.1152\/ajprenal.2001.280.1.F1","article-title":"Ammonium carriers in medullary thick ascending limb","volume":"280","author":"Attmane-Elakeb","year":"2001","journal-title":"Am J Physiol Renal Physiol"},{"key":"B5-20240826","doi-asserted-by":"crossref","first-page":"5406","DOI":"10.1073\/pnas.0813231106","article-title":"Relative CO2\/NH3 selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG","volume":"106","author":"Musa-Aziz","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B6-20240826","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/nature07518","article-title":"A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility","volume":"456","author":"Biver","year":"2008","journal-title":"Nature"},{"key":"B7-20240826","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1172\/JCI36581","article-title":"NHE4 is critical for the renal handling of ammonia in rodents","volume":"120","author":"Bourgeois","year":"2010","journal-title":"J Clin Invest"},{"key":"B8-20240826","doi-asserted-by":"crossref","first-page":"F341","DOI":"10.1152\/ajprenal.00104.2001","article-title":"Chronic metabolic acidosis upregulates rat kidney Na+-HCO3 \u2212 cotransporters NBCn1 and NBC3 but not NBC1","volume":"282","author":"Kwon","year":"2002","journal-title":"Am J Physiol Renal Physiol"},{"key":"B9-20240826","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/35014615","article-title":"An electroneutral sodium\/bicarbonate cotransporter NBCn1 and associated sodium channel","volume":"405","author":"Choi","year":"2000","journal-title":"Nature"},{"key":"B10-20240826","doi-asserted-by":"crossref","first-page":"16569","DOI":"10.1074\/jbc.274.23.16569","article-title":"Cloning, tissue distribution, genomic organization, and functional characterization of NBC3, a new member of the sodium bicarbonate cotransporter family","volume":"274","author":"Pushkin","year":"1999","journal-title":"J Biol Chem"},{"key":"B11-20240826","doi-asserted-by":"crossref","first-page":"C591","DOI":"10.1152\/ajpcell.00281.2007","article-title":"Antibody-independent localization of the electroneutral Na+-HCO3 \u2212 cotransporter NBCn1 (slc4a7) in mice","volume":"294","author":"Boedtkjer","year":"2008","journal-title":"Am J Physiol Cell Physiol"},{"key":"B12-20240826","doi-asserted-by":"crossref","first-page":"F901","DOI":"10.1152\/ajprenal.2000.279.5.F901","article-title":"Immunolocalization of electroneutral Na+-HCO3 \u2212 cotransporter in rat kidney","volume":"279","author":"Vorum","year":"2000","journal-title":"Am J Physiol Renal Physiol"},{"key":"B13-20240826","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s00424-004-1303-4","article-title":"Functional up-regulation of basolateral Na+-dependent HCO3 \u2212 transporter NBCn1 in medullary thick ascending limb of K+-depleted rats","volume":"448","author":"Jakobsen","year":"2004","journal-title":"Pflugers Arch"},{"key":"B14-20240826","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1113\/jphysiol.2003.046474","article-title":"Basolateral Na+-dependent HCO3 \u2212 transporter NBCn1-mediated HCO3 \u2212 influx in rat medullary thick ascending limb","volume":"555","author":"Odgaard","year":"2004","journal-title":"J Physiol"},{"key":"B15-20240826","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.2174\/138161212799504830","article-title":"Physiology, pharmacology and pathophysiology of the pH regulatory transport proteins NHE1 and NBCn1: Similarities, differences, and implications for cancer therapy","volume":"18","author":"Boedtkjer","year":"2012","journal-title":"Curr Pharm Des"},{"key":"B16-20240826","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1002\/cmdc.201200335","article-title":"Gram-scale solution-phase synthesis of selective sodium bicarbonate co-transport inhibitor S0859: In vitro efficacy studies in breast cancer cells","volume":"7","author":"Larsen","year":"2012","journal-title":"ChemMedChem"},{"key":"B17-20240826","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1039\/C5MD00367A","article-title":"Synthesis of N-cyano-substituted sulfilimine and sulfoximine derivatives of S0859 and their biological evaluation as sodium bicarbonate co-transport inhibitors","volume":"6","author":"Steinkamp","year":"2015","journal-title":"MedChemComm"},{"key":"B18-20240826","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1161\/CIRCULATIONAHA.110.015974","article-title":"Disruption of Na+,HCO3 \u2212 cotransporter NBCn1 (slc4a7) inhibits NO-mediated vasorelaxation, smooth muscle Ca2+ sensitivity, and hypertension development in mice","volume":"124","author":"Boedtkjer","year":"2011","journal-title":"Circulation"},{"key":"B19-20240826","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/BF00582110","article-title":"A modified system for in vitro perfusion of isolated renal tubules","volume":"389","author":"Greger","year":"1981","journal-title":"Pflugers Arch"},{"key":"B20-20240826","first-page":"321","article-title":"Perfusion of isolated renal tubules","volume":"45","author":"Burg","year":"1972","journal-title":"Yale J Biol Med"},{"key":"B21-20240826","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1021\/bi00578a012","article-title":"Intracellular pH measurements in Ehrlich ascites tumor cells utilizing spectroscopic probes generated in situ","volume":"18","author":"Thomas","year":"1979","journal-title":"Biochemistry"},{"key":"B22-20240826","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1152\/physrev.1981.61.2.296","article-title":"Intracellular pH","volume":"61","author":"Roos","year":"1981","journal-title":"Physiol Rev"},{"key":"B23-20240826","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1093\/cvr\/cvw079","article-title":"Na+,HCO3 \u2212-cotransporter NBCn1 increases pHi gradients, filopodia, and migration of smooth muscle cells and promotes arterial remodelling","volume":"111","author":"Boedtkjer","year":"2016","journal-title":"Cardiovasc Res"},{"key":"B24-20240826","doi-asserted-by":"crossref","first-page":"H172","DOI":"10.1152\/ajpheart.00713.2005","article-title":"An anti-NH2-terminal antibody localizes NBCn1 to heart endothelia and skeletal and vascular smooth muscle cells","volume":"290","author":"Damkier","year":"2006","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B25-20240826","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/ki.2013.14","article-title":"Rapid dephosphorylation of the renal sodium chloride cotransporter in response to oral potassium intake in mice","volume":"83","author":"Sorensen","year":"2013","journal-title":"Kidney Int"},{"key":"B26-20240826","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/S0009-9120(72)80014-6","article-title":"The rapid determination of urinary titratable acid and ammonium and evaluation of freezing as a method of preservation","volume":"5","author":"Chan","year":"1972","journal-title":"Clin Biochem"},{"key":"B27-20240826","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1681\/ASN.V2177","article-title":"Role of countercurrent multiplication in renal ammonium handling: Regulation of medullary ammonium accumulation","volume":"2","author":"Packer","year":"1991","journal-title":"J Am Soc Nephrol"},{"key":"B28-20240826","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1161\/01.RES.0000204750.04971.76","article-title":"NBCn1 (slc4a7) mediates the Na+-dependent bicarbonate transport important for regulation of intracellular pH in mouse vascular smooth muscle cells","volume":"98","author":"Boedtkjer","year":"2006","journal-title":"Circ Res"},{"key":"B29-20240826","doi-asserted-by":"crossref","first-page":"5569","DOI":"10.1038\/s41388-018-0353-6","article-title":"Na+,HCO3 \u2212-cotransporter NBCn1 (Slc4a7) accelerates ErbB2-induced breast cancer development and tumor growth in mice","volume":"37","author":"Lee","year":"2018","journal-title":"Oncogene"},{"key":"B30-20240826","doi-asserted-by":"crossref","first-page":"F1244","DOI":"10.1152\/ajprenal.00176.2004","article-title":"Transepithelial HCO3\u2212 absorption is defective in renal thick ascending limbs from Na+\/H+ exchanger NHE1 null mutant mice","volume":"287","author":"Good","year":"2004","journal-title":"Am J Physiol Renal Physiol"},{"key":"B31-20240826","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/apha.12877","article-title":"Extracellular acidosis and very low [Na+] inhibit NBCn1- and NHE1-mediated net acid extrusion from mouse vascular smooth muscle cells","volume":"221","author":"Bonde","year":"2017","journal-title":"Acta Physiol (Oxf)"},{"key":"B32-20240826","doi-asserted-by":"crossref","first-page":"8146","DOI":"10.1074\/jbc.M113.455386","article-title":"Splice cassette II of NBCn1 (slc4a7) interacts with calcineurin A: Implications for transporter activity and intracellular pH control during rat artery contractions","volume":"288","author":"Danielsen","year":"2013","journal-title":"J Biol Chem"},{"key":"B33-20240826","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1113\/jphysiol.2012.249664","article-title":"Sarcolemmal localisation of Na+\/H+ exchange and Na+-HCO3 \u2212 co-transport influences the spatial regulation of intracellular pH in rat ventricular myocytes","volume":"591","author":"Garciarena","year":"2013","journal-title":"J Physiol"},{"key":"B34-20240826","doi-asserted-by":"crossref","first-page":"F397","DOI":"10.1152\/ajprenal.00162.2005","article-title":"Renal expression of the ammonia transporters, Rhbg and Rhcg, in response to chronic metabolic acidosis","volume":"290","author":"Seshadri","year":"2006","journal-title":"Am J Physiol Renal Physiol"},{"key":"B35-20240826","doi-asserted-by":"crossref","first-page":"F11","DOI":"10.1152\/ajprenal.00554.2010","article-title":"Role of NH3 and NH4 + transporters in renal acid-base transport","volume":"300","author":"Weiner","year":"2011","journal-title":"Am J Physiol Renal Physiol"}],"container-title":["Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1681\/ASN.2019060613","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:24:35Z","timestamp":1786130675000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1681\/ASN.2019060613"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,7]]},"references-count":35,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1681\/asn.2019060613","relation":{},"ISSN":["1046-6673","1533-3450"],"issn-type":[{"value":"1046-6673","type":"print"},{"value":"1533-3450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,7]]},"assertion":[{"value":"2020-06-20","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-23","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}