AbstractWe discovered high Na⁺ and water content in the skin of newborn Sprague–Dawley rats, which reduced ~ 2.5-fold by 7 days of age, indicating rapid changes in extracellular volume (ECV). Equivalent changes in ECV post birth were also observed in C57Bl/6 J mice, with a fourfold reduction over 7 days, to approximately adult levels. This established the generality of increased ECV at birth. We investigated early sodium and water handling in neonates from a second rat strain, Fischer, and an Hsd11b2-knockout rat modelling the syndrome of apparent mineralocorticoid excess (SAME). Despite Hsd11b2^−/− animals exhibiting lower skin Na⁺ and water levels than controls at birth, they retained ~ 30% higher Na⁺ content in their pelts at the expense of K⁺ thereafter. Hsd11b2^−/− neonates exhibited incipient hypokalaemia from 15 days of age and became increasingly polydipsic and polyuric from weaning. As with adults, they excreted a high proportion of ingested Na⁺ through the kidney, (56.15 ± 8.21% versus control 34.15 ± 8.23%; n = 4; P < 0.0001), suggesting that changes in nephron electrolyte transporters identified in adults, by RNA-seq analysis, occur by 4 weeks of age. Our data reveal that Na⁺ imbalance in the Hsd11b2^−/− neonate leads to excess Na⁺ storage in skin and incipient hypokalaemia, which, together with increased, glucocorticoid-induced Na⁺ uptake in the kidney, then contribute to progressive, volume contracted, salt-sensitive hypertension. Skin Na⁺ plays an important role in the development of SAME but, equally, may play a key physiological role at birth, supporting post-natal growth, as an innate barrier to infection or as a rudimentary kidney.