Endocrine Abstracts (2010) 22 P257

Mineralocorticoid pathway in newborns: evidence for a physiological renal aldosterone unresponsiveness

Laetitia Martinerie1, Say Viengchareun1, Pascal Boileau2 & Marc Lombes1

1INSERM U693, Le Kremlin Bicetre, France; 2Hopital Antoine Beclere, Clamart, France.

Aldosterone is the main steroid hormone controlling sodium homeostasis in human. During the neonatal period, full term newborns and more specifically premature infants, are subjected to an impaired renal capacity to reabsorb sodium, responsible for sodium loss and failure to thrive which could be linked to a renal aldosterone unresponsiveness at birth. A clinical prospective study on 50 newborns and their mothers, revealed high aldosterone and renin levels in umbilical blood samples compared to maternal plasma levels. This contrasted with signs of functional hypoaldosteronism in newborns: hyponatremia, hyperkalemia and urinary sodium loss, consistent with a partial aldosterone resistance at birth. We also established a reference value for neonatal urinary aldosterone concentration which represents the best index for accurate evaluation of mineralocorticoid sensitivity at birth.

Given that the Mineralocorticoid Receptor (MR) mediates most renal aldosterone effects, we investigated the ontogeny of renal MR expression by gene expression studies and immunodetection experiments during development in mouse and human. We show that MR mRNA and protein expression follows a biphasic temporal profile with a transient peak during gestation, a low expression at birth and a progressive increase during the postnatal period. This cyclic renal expression was specific to the mineralocorticoid signaling pathway and could account for the partial aldosterone resistance observed at birth.

We have documented an aldosterone unresponsiveness at birth which was accompanied by a low renal MR expression level. Molecular mechanisms involved in the regulation of MR expression are under investigation. A multicenter clinical investigation program, supported by a French national PHRC grant, is currently ongoing in order to evaluate the intensity of aldosterone resistance as a function of gestational age and to examine its evolution throughout the first year of life. This work could ultimately lead to new therapeutic strategies for the management of sodium loss in preterms and neonates.

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