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NBCn1 and NBCn2 are present in the basolateral mTAL, where NBCn1 promotes NH4<\/jats:sub>+<\/jats:sup> shunting. IRBIT and L\u2010IRBIT (the IRBITs) are two powerful activators of certain acid\u2010base transporters. Here we use western blotting and immunofluorescence to examine the effects of multiple acid\u2010base and electrolyte disturbances on expression of NBCn1, NBCn2 and the IRBITs in rat kidney. We also use electrophysiology to examine the functional effects of IRBITs on NBCn1 and NBCn2 in Xenopus<\/jats:italic> oocytes. NH4<\/jats:sub>Cl\u2010induced metabolic acidosis (MAc) substantially increases protein expression of NBCn1 and NBCn2 in the outer medulla (OM) of rat kidney. Surprisingly, NaHCO3<\/jats:sub>\u2010induced metabolic alkalosis (MAlk) and high\u2010salt diet (HSD) also increase expression of NBCn1 and NBCn2 (effect of NaHCO3<\/jats:sub>\u00a0>\u00a0HSD). Moreover, all three challenges generally increase OM expression of the IRBITs. In Xenopus<\/jats:italic> oocytes, the IRBITs substantially increase the activities of NBCn1 and NBCn2. We propose that upregulation of basolateral NBCn1 and NBCn2 plus the IRBITs in the mTAL: (1) promotes NH4<\/jats:sub>+<\/jats:sup> shunting by increasing basolateral HCO3<\/jats:sub>\u2013<\/jats:sup> uptake to neutralize apical NH4<\/jats:sub>+<\/jats:sup> uptake during MAc; (2) inhibits HCO3<\/jats:sub>\u2013<\/jats:sup> reabsorption during MAlk by opposing HCO3<\/jats:sub>\u2212<\/jats:sup> efflux via the basolateral anion exchanger AE2; and (3) inhibits NaCl reabsorption by mediating (with AE2) net NaCl backflux into the mTAL cell during HSD. Thus, NBCn1, NBCn2 and the IRBITs are at the nexus of the regulatory pathways for multiple renal transport processes.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp279009","type":"journal-article","created":{"date-parts":[[2020,5,2]],"date-time":"2020-05-02T12:59:42Z","timestamp":1588424382000},"page":"3395-3415","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Multiple acid\u2010base and electrolyte disturbances upregulate NBCn1, NBCn2, IRBIT and L\u2010IRBIT in the mTAL"],"prefix":"10.1113","volume":"598","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1625-8092","authenticated-orcid":false,"given":"Jin\u2010Lin","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of Ministry of Education School of Life Science & Technology Huazhong University of Science & Technology Wuhan Hubei 430074 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Biochemistry Case Western Reserve University School of Medicine Cleveland OH 44106 USA"},{"name":"Department of Physiology and Biophysics School of Medicine University at Buffalo: The State University of New York Buffalo NY 14214 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raif","family":"Musa\u2010Aziz","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Department of Medicine Department of Biochemistry Case Western Reserve University School of Medicine Cleveland OH 44106 USA"},{"name":"Department of Physiology and Biophysics Institute of Biomedical Sciences University of Sao Paulo Sao Paulo 05508\u2010900 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7257-3690","authenticated-orcid":false,"given":"Jacob","family":"Popple","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Department of Medicine Department of Biochemistry Case Western Reserve University School of Medicine Cleveland OH 44106 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Min","family":"Guo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of Ministry of Education School of Life Science & Technology Huazhong University of Science & Technology Wuhan Hubei 430074 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian\u2010Xin","family":"Min","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of Ministry of Education School of Life Science & Technology Huazhong University of Science & Technology Wuhan Hubei 430074 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Xia","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of Ministry of Education School of Life Science & Technology Huazhong University of Science & Technology Wuhan Hubei 430074 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