title: Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences.
abstract: Sex differences have been identified in various biological processes, including hypertension. The mineralocorticoid signaling pathway is an important contributor to early arterial hypertension, however its sex-specific expression has been scarcely studied, particularly with respect to the kidney. Basal systolic blood pressure (SBP) and heart rate (HR) were measured in adult male and female mice. Renal gene expression studies of major players of mineralocorticoid signaling were performed at different developmental stages in male and female mice using reverse transcription quantitative PCR (RT-qPCR), and were compared to those of the same genes in the lung, another mineralocorticoid epithelial target tissue that regulates ion exchange and electrolyte balance. The role of sex hormones in the regulation of these genes was also investigated in differentiated KC3AC1 renal cells. Additionally, renal expression of the 11 β-hydroxysteroid dehydrogenase type 2 (11βHSD2) protein, a regulator of mineralocorticoid specificity, was measured by immunoblotting and its activity was indirectly assessed in the plasma using liquid-chromatography coupled to mass spectrometry in tandem (LC-MSMS) method. SBP and HR were found to be significantly lower in females compared to males. This was accompanied by a sex- and tissue-specific expression profile throughout renal development of the mineralocorticoid target genes serum and glucocorticoid-regulated kinase 1 (Sgk1) and glucocorticoid-induced leucine zipper protein (Gilz), together withHsd11b2, Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably forGilzmRNA expression. We demonstrate a tissue-specific, sex-dependent and developmentally-regulated pattern of expression of the mineralocorticoid pathway that could have important implications in physiology and pathology.
authors.affiliation: Inserm U1185, Univ Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. ldumeige@u-psud.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Dumeige
authors.affiliation: Inserm U1185, Univ Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. caroline.storey@aphp.fr.|Service d'Endocrinologie Pédiatrique, Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, F-75019 Paris, France. caroline.storey@aphp.fr.|Faculté de Médecine Paris Diderot, Université Paris Diderot, Sorbonne Paris Cité, F-75019 Paris, France. caroline.storey@aphp.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Storey
authors.affiliation: Inserm, UMR_S938, Centre de Recherche Saint-Antoine, F-75012 Paris, France. lyvianne.decourtye@inserm.fr.
authors.forename: Lyvianne
authors.initials: L
authors.lastname: Decourtye
authors.affiliation: Inserm U1185, Univ Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. melanie.nehlich@yahoo.fr.|PremUp Foundation, F-75005 Paris, France. melanie.nehlich@yahoo.fr.
authors.forename: Melanie
authors.initials: M
authors.lastname: Nehlich
authors.affiliation: Inserm U1185, Univ Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. christophe.lhadj@u-psud.fr.|PremUp Foundation, F-75005 Paris, France. christophe.lhadj@u-psud.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lhadj
authors.affiliation: Inserm U1185, Univ Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. say.viengchareun@u-psud.fr.
authors.forename: Say
authors.initials: S
authors.lastname: Viengchareun
authors.affiliation: Inserm, UMR_S938, Centre de Recherche Saint-Antoine, F-75012 Paris, France. laurent.kappeler@inserm.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Kappeler
authors.affiliation: Inserm U1185, Univ Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. marc.lombes@u-psud.fr.|PremUp Foundation, F-75005 Paris, France. marc.lombes@u-psud.fr.|Faculté de Médecine Paris-Sud, UMR-S1185, Université Paris-Sud 11, F-94276 Le Kremlin-Bicêtre, France. marc.lombes@u-psud.fr.|Service d'Endocrinologie et Maladies de la Reproduction, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, F-94275 Le Kremlin Bicêtre, France. marc.lombes@u-psud.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.affiliation: Inserm U1185, Univ Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. laetitia.martinerie@aphp.fr.|Service d'Endocrinologie Pédiatrique, Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, F-75019 Paris, France. laetitia.martinerie@aphp.fr.|Faculté de Médecine Paris Diderot, Université Paris Diderot, Sorbonne Paris Cité, F-75019 Paris, France. laetitia.martinerie@aphp.fr.|PremUp Foundation, F-75005 Paris, France. laetitia.martinerie@aphp.fr.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Martinerie
mesh_terms: D000818:Animals; D015415:Biomarkers; D001794:Blood Pressure / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D012739:Gonadal Steroid Hormones; D006339:Heart Rate / Q000235:genetics; D007668:Kidney / Q000196:embryology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008901:Mineralocorticoids / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D038081:Organogenesis / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D012737:Sex Factors; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D012739:Gonadal Steroid Hormones; D008901:Mineralocorticoids; D018161:Receptors, Mineralocorticoid
keywords: gene expression; hypertension; mineralocorticoid signaling pathway; sexual dimorphism