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Two downstream effectors of cAMP are PKA and exchange protein directly activated by cAMP (Epac), which, unlike PKA, is often linked to elevation of [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    . While both Epac isoforms (Epac1 and Epac2) are expressed along the nephron, their relevance in the kidney remains obscure. We combined ratiometric calcium imaging with quantitative immunoblotting, immunofluorescent confocal microscopy, and balance studies in mice lacking Epac1 or Epac2 to determine the role of Epac in renal water\u2010solute handling. Epac1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    and Epac2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice developed polyuria despite elevated arginine vasopressin levels. We did not detect major deficiencies in arginine vasopressin [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    signaling in split\u2010opened collecting ducts or decreases in aquaporin water channel type 2 levels. Instead, sodium\u2010hydrogen exchanger type 3 levels in the proximal tubule were dramatically reduced in Epac1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    and Epac2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Water deprivation revealed persisting polyuria, impaired urinary concentration ability, and augmented urinary excretion of Na\n                    <jats:sup>+<\/jats:sup>\n                    and urea in both mutant mice. In summary, we report a nonredundant contribution of Epac isoforms to renal function. Deletion of Epac1 and Epac2 decreases sodium\u2013hydrogen exchanger type 3 expression in the proximal tubule, leading to polyuria and osmotic diuresis.\u2014Cherezova, A., Tomilin, V., Buncha, V., Zaika, O., Ortiz, P. A., Mei, F., Cheng, X., Mamenko, M., Pochynyuk, O. Urinary concentrating defect in mice lacking Epac1 or Epac2. FASEB J. 33, 2156\u20132170 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201800435r","type":"journal-article","created":{"date-parts":[[2018,9,25]],"date-time":"2018-09-25T15:53:15Z","timestamp":1537890795000},"page":"2156-2170","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Urinary concentrating defect in mice lacking Epac1 or Epac2"],"prefix":"10.1096","volume":"33","author":[{"given":"Alena","family":"Cherezova","sequence":"first","affiliation":[{"name":"Department of Physiology Medical College of Georgia Augusta University Augusta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viktor","family":"Tomilin","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Pharmacology The 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