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We hypothesized that renal NHE3 is important for the acid-base response during K\n                    <jats:sup>+<\/jats:sup>\n                    depletion. To test this, we utilized kidney-specific NHE3 knockout (NHE3\n                    <jats:sup>KS\u2212KO<\/jats:sup>\n                    ) mice. Following 10 days of a K\n                    <jats:sup>+<\/jats:sup>\n                    -deficient diet (&lt;\u200930 ppm), NHE3\n                    <jats:sup>KS\u2212KO<\/jats:sup>\n                    mice exhibited exacerbated hypokalemia compared to control mice, despite near complete elimination of urinary K\n                    <jats:sup>+<\/jats:sup>\n                    excretion and comparable levels of ROMK and BK\u03b1 protein abundance in both genotypes. Control and NHE3\n                    <jats:sup>KS\u2212KO<\/jats:sup>\n                    mice developed hypernatremia secondary to a urinary concentrating defect; however, this was associated with a\u2009~\u20092-fold greater fluid intake in NHE3\n                    <jats:sup>KS\u2212KO<\/jats:sup>\n                    mice. These effects occurred without changes in glomerular filtration rate. Both genotypes developed metabolic acidosis, which was significantly more severe in NHE3\n                    <jats:sup>KS\u2212KO<\/jats:sup>\n                    mice. This exacerbated acidosis correlated with a\u2009~\u200960% lower mRNA expression of glutamine synthetase and a lower urinary NH\n                    <jats:sub>4<\/jats:sub>\n                    <jats:sup>+<\/jats:sup>\n                    \/creatinine ratio. Furthermore, early histopathological signs of hypokalemic nephropathy were observed exclusively in some of the NHE3\n                    <jats:sup>KS\u2212KO<\/jats:sup>\n                    mice. Our findings demonstrate that renal NHE3 attenuates the severity of hypokalemia and metabolic acidosis during K\n                    <jats:sup>+<\/jats:sup>\n                    restriction, possibly via NH\n                    <jats:sub>4<\/jats:sub>\n                    <jats:sup>+<\/jats:sup>\n                    formation\/transport, which might accelerate the development of hypokalemic nephropathy.\n                  <\/jats:p>","DOI":"10.1007\/s00424-026-03178-9","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T02:35:27Z","timestamp":1780972527000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Renal NHE3 is required to limit hypokalemia and metabolic acidosis during dietary potassium deficiency"],"prefix":"10.1007","volume":"478","author":[{"given":"Jennifer","family":"Nogueira Coelho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Hayslip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca Zoe","family":"Halter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sima","family":"Al-Masri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana C. 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