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Low Renal Mineralocorticoid Receptor Expression at Birth Contributes to Partial Aldosterone Resistance in Neonates

Institut National de la Santé et de la Recherche Médicale (L.M., S.V., G.M., M.L.), Unité 693, Le Kremlin-Bicêtre F-94276, France; Université Paris-Sud 11 (L.M., S.V., G.M., M.L.), Faculté de Médecine Paris-Sud, Unité Mixte de Recherche-S693, Le Kremlin-Bicêtre F-94276, France; Université Paris-Diderot et Assistance Publique-Hôpitaux de Paris (A.-L.D.), Hôpital Robert Debré, Service de Biologie du Développement, Paris F-75019, France; Assistance Publique-Hôpitaux de Paris (F.J.), Hôpital Necker-Enfants Malades, Service d’AnatomoPathologie, Paris F-75015, France; Centre Hospitalier Intercommunal de Créteil (M.S.), Service d’AnatomoPathologie, Créteil F-94010, France; Assistance Publique-Hôpitaux de Paris, Hôpital Antoine Béclère, Service d’AnatomoPathologie (S.P.) et de Pédiatrie et Réanimation Néonatales (P.B.), Clamart F-92141, France; and Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service de Pharmacogénétique, Biochimie Moléculaire et Hormonologie (G.M.) et d’Endocrinologie et Maladies de la Reproduction (M.L.), Le Kremlin Bicêtre F-94275, France

Address all correspondence and requests for reprints to: Dr. Marc Lombes, M.D., Ph.D., Inserm U693, Faculté de Médecine Paris-Sud, 63, rue Gabriel Péri, 94276 Le Kremlin Bicêtre Cedex, France. E-mail: marc.lombes{at}u-psud.fr.

The human neonatal period is characterized by renal immaturity with impaired capacity to regulate water and sodium homeostasis, resembling partial aldosterone resistance. Because aldosterone effects are mediated by the mineralocorticoid receptor (MR), we postulated that this hormonal unresponsiveness could be related to low MR expression in the distal nephron. We measured aldosterone and renin levels in umbilical cord blood of healthy newborns. We used quantitative real-time PCR and immunohistochemistry to analyze the expression of MR and key players of the mineralocorticoid signaling pathway during human and mouse renal development. High aldosterone and renin levels were found at birth. MR mRNA was detected in mouse kidney at d 16 postcoitum, peaking at d 18 postcoitum, but its expression was surprisingly very low at birth, rising progressively afterward. Similar biphasic temporal expression was observed during human renal embryogenesis, with a transient expression between 15 and 24 wk of gestation but an undetectable immunoreactive MR in late gestational and neonatal kidneys. This cyclic MR expression was tightly correlated with the evolution of the 11β-hydroxysteroid dehydrogenase type 2 and the epithelial sodium channel -subunit. In contrast, glucocorticoid and vasopressin receptors and aquaporin 2 followed a progressive and sustained evolution during renal maturation. Our study provides the first evidence for a low renal MR expression level at birth, despite high aldosterone levels, which could account for compromised postnatal sodium handling. Elucidation of regulatory mechanisms governing MR expression should lead to new strategies for the management of sodium waste in preterms and neonates.