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NHE1 also transports Li<jats:sup>+<\/jats:sup>, preferably compared to NHE3, and the lack of NHE3 does not affect renal Li<jats:sup>+<\/jats:sup> clearance. Therefore, we hypothesized that NHE1 plays a critical role in mediating renal Li<jats:sup>+<\/jats:sup> effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated mice lacking NHE1 in epithelial cells throughout the kidney tubule\/collecting duct (NHE1<jats:sup>KS\u2010KO<\/jats:sup>). Physiological phenotyping of NHE1<jats:sup>loxlox<\/jats:sup> and NHE1<jats:sup>KS\u2010KO<\/jats:sup> mice was performed under a control diet and after mice received a LiCl\u2010containing diet for 4\u2009weeks. Tissue was harvested at baseline and at the end of the experimental period for quantification of NHE1 and aquaporin\u20102 abundances.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In NHE1<jats:sup>loxlox<\/jats:sup> mice, NHE1 localized to the basolateral membrane of the distal parts of the nephron and collecting duct (principal and intercalated cells). No NHE1 was observed in tubules or collecting ducts of NHE1<jats:sup>KS\u2010KO<\/jats:sup> mice, and no physiological differences were observed between genotypes under baseline conditions. While both genotypes developed a urinary concentrating defect in response to Li<jats:sup>+<\/jats:sup>, NHE1<jats:sup>KS\u2010KO<\/jats:sup> mice drank twice as much, and their urine osmolality was twice as dilute compared with NHE1<jats:sup>loxlox<\/jats:sup> mice. This was associated with greater hypernatremia in NHE1<jats:sup>KS\u2010KO<\/jats:sup> mice. Reduced AQP2 and phosphorylation at serine 256 were observed in NHE1<jats:sup>KS\u2010KO<\/jats:sup> mice. In association with this, AQP2 was more broadly distributed throughout the cytoplasm of NHE1<jats:sup>KS\u2010KO<\/jats:sup> mice, relative to the defined apical membrane AQP2 distribution seen in NHE1<jats:sup>loxlox<\/jats:sup> animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Lack of NHE1 interferes with the Li<jats:sup>+<\/jats:sup> handling in principal cells, resulting in exacerbated Li<jats:sup>+<\/jats:sup>\u2010induced NDI.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.70029","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T06:44:44Z","timestamp":1742798684000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Lack of renal <scp>NHE1<\/scp> exacerbates lithium\u2010induced nephrogenic diabetes insipidus"],"prefix":"10.1111","volume":"241","author":[{"given":"Gabriella","family":"Blanco","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology, Morsani College of Medicine University of South Florida  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxiang","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of New Mexico  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linto","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology, Morsani College of Medicine University of South Florida  Tampa Florida USA"},{"name":"James A. 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