Abnormal neonatal sodium handling in skin precedes hypertension in the SAME rat

Linda Mullins, Jessica Ivy, Mairi Ward, Olav Tenstad, Helge Wiig, Kento Kitada, Jon Manning, Natalia Rakova, Dominik Muller, John Mullins

Research output: Contribution to journalArticlepeer-review

Abstract

We 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/6J mice, with a 4-fold 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.
Original languageEnglish
Article number473
Pages (from-to)897
Number of pages910
JournalPflügers Archiv European Journal of Physiology
DOIs
Publication statusPublished - 24 May 2021

Keywords

  • Hsd11b2
  • knockout
  • hypertension
  • newborn
  • neonatal
  • rat
  • salt-sensitive
  • Skin

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