Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences

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 with Hsd11b2, Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably for Gilz mRNA 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

Impact of Prematurity and Fetal Growth Restriction on Renal Corticosteroid Signaling Pathways : Neonatal Adaptation and Fetal Programming of High Blood Pressure

La prématurité et la restriction de croissance fœtale (RCF) sont deux pathologies néonatales fréquentes, qui ont en commun des difficultés d'adaptation à la naissance, avec le développement d'une tubulopathie chez le prématuré, et le développement d'une hypertension artérielle (HTA) a l'âge adulte. L’objectif de ce travail était d’évaluer l'implication des voies de signalisation corticostéroïdes rénales dans la survenue de ces complications dans un modèle murin de prématurité induite par des lipopolysaccharides, et un modèle de RCF par exposition périnatale a la dexaméthasone. Dans ce travail nous avons montré que ces deux pathologies programment la survenue d’une HTA à l’âge adulte chez les mâles, associée à des altérations franches de la signalisation corticostéroïde rénale en période périnatale et une augmentation de la sensibilité rénale aux glucocorticoïdes à l’âge adulte. Dans le modèle de prématurité, nous avons identifié la transmission transgénérationelle d’anomalies de régulation de la pression artérielle chez les mâles jusqu’à la 3ème génération de souris, associée à une hypométhylation du promoteur de GILZ et une augmentation d’expression de GILZ. Notre étude a permis l’identification de potentiels mécanismes moléculaires impliqués dans la programmation fœtale de l’HTA, sur plusieurs générations, ce qui pourrait aboutir à une meilleure prise en charge des patients nés prématurés ou avec une RCF, et de leurs descendants.Preterm birth and fetal growth restriction (IUGR) are prevalent neonatal diseases, which both induce poor perinatal adaptation, including the development of tubulopathy in premature infants, and the development of high blood pressure in adults. The objective of this work was to evaluate the involvement of renal corticosteroid signaling pathways in the development of these complications in a lipopolysaccharide-induced mouse model of preterm birth, and a dexamethasone-induced model of IUGR. In this work, we have shown that these two pathologies program the development of hypertension in former preterm and IUGR male mice, associated with strong alterations of renal corticosteroid signaling in the perinatal period, and an increase in renal sensitivity to glucocorticoids in adulthood. Moreover, we have identified a transgenerational inheritance of altered blood pressure regulation induced by preterm birth, in males, up to the 3rd generation of mice, associated with GILZ promoter hypomethylation and increased GILZ expression.Our study has identified potential molecular mechanisms involved in the fetal programming of hypertension, over several generations. These findings could facilitate better management of patients born prematurel

Impact de la prématurité et de la restriction de croissance fœtale sur les voies de signalisation corticostéroïdes rénales : adaptation néonatale et programmation fœtale de l’hypertension artérielle

Preterm birth and fetal growth restriction (IUGR) are prevalent neonatal diseases, which both induce poor perinatal adaptation, including the development of tubulopathy in premature infants, and the development of high blood pressure in adults. The objective of this work was to evaluate the involvement of renal corticosteroid signaling pathways in the development of these complications in a lipopolysaccharide-induced mouse model of preterm birth, and a dexamethasone-induced model of IUGR. In this work, we have shown that these two pathologies program the development of hypertension in former preterm and IUGR male mice, associated with strong alterations of renal corticosteroid signaling in the perinatal period, and an increase in renal sensitivity to glucocorticoids in adulthood. Moreover, we have identified a transgenerational inheritance of altered blood pressure regulation induced by preterm birth, in males, up to the 3rd generation of mice, associated with GILZ promoter hypomethylation and increased GILZ expression.Our study has identified potential molecular mechanisms involved in the fetal programming of hypertension, over several generations. These findings could facilitate better management of patients born prematurelyLa prématurité et la restriction de croissance fœtale (RCF) sont deux pathologies néonatales fréquentes, qui ont en commun des difficultés d'adaptation à la naissance, avec le développement d'une tubulopathie chez le prématuré, et le développement d'une hypertension artérielle (HTA) a l'âge adulte. L’objectif de ce travail était d’évaluer l'implication des voies de signalisation corticostéroïdes rénales dans la survenue de ces complications dans un modèle murin de prématurité induite par des lipopolysaccharides, et un modèle de RCF par exposition périnatale a la dexaméthasone. Dans ce travail nous avons montré que ces deux pathologies programment la survenue d’une HTA à l’âge adulte chez les mâles, associée à des altérations franches de la signalisation corticostéroïde rénale en période périnatale et une augmentation de la sensibilité rénale aux glucocorticoïdes à l’âge adulte. Dans le modèle de prématurité, nous avons identifié la transmission transgénérationelle d’anomalies de régulation de la pression artérielle chez les mâles jusqu’à la 3ème génération de souris, associée à une hypométhylation du promoteur de GILZ et une augmentation d’expression de GILZ. Notre étude a permis l’identification de potentiels mécanismes moléculaires impliqués dans la programmation fœtale de l’HTA, sur plusieurs générations, ce qui pourrait aboutir à une meilleure prise en charge des patients nés prématurés ou avec une RCF, et de leurs descendants

Impact de la prématurité et de la restriction de croissance fœtale sur les voies de signalisation corticostéroïdes rénales : adaptation néonatale et programmation fœtale de l’hypertension artérielle

Preterm birth and fetal growth restriction (IUGR) are prevalent neonatal diseases, which both induce poor perinatal adaptation, including the development of tubulopathy in premature infants, and the development of high blood pressure in adults. The objective of this work was to evaluate the involvement of renal corticosteroid signaling pathways in the development of these complications in a lipopolysaccharide-induced mouse model of preterm birth, and a dexamethasone-induced model of IUGR. In this work, we have shown that these two pathologies program the development of hypertension in former preterm and IUGR male mice, associated with strong alterations of renal corticosteroid signaling in the perinatal period, and an increase in renal sensitivity to glucocorticoids in adulthood. Moreover, we have identified a transgenerational inheritance of altered blood pressure regulation induced by preterm birth, in males, up to the 3rd generation of mice, associated with GILZ promoter hypomethylation and increased GILZ expression.Our study has identified potential molecular mechanisms involved in the fetal programming of hypertension, over several generations. These findings could facilitate better management of patients born prematurelyLa prématurité et la restriction de croissance fœtale (RCF) sont deux pathologies néonatales fréquentes, qui ont en commun des difficultés d'adaptation à la naissance, avec le développement d'une tubulopathie chez le prématuré, et le développement d'une hypertension artérielle (HTA) a l'âge adulte. L’objectif de ce travail était d’évaluer l'implication des voies de signalisation corticostéroïdes rénales dans la survenue de ces complications dans un modèle murin de prématurité induite par des lipopolysaccharides, et un modèle de RCF par exposition périnatale a la dexaméthasone. Dans ce travail nous avons montré que ces deux pathologies programment la survenue d’une HTA à l’âge adulte chez les mâles, associée à des altérations franches de la signalisation corticostéroïde rénale en période périnatale et une augmentation de la sensibilité rénale aux glucocorticoïdes à l’âge adulte. Dans le modèle de prématurité, nous avons identifié la transmission transgénérationelle d’anomalies de régulation de la pression artérielle chez les mâles jusqu’à la 3ème génération de souris, associée à une hypométhylation du promoteur de GILZ et une augmentation d’expression de GILZ. Notre étude a permis l’identification de potentiels mécanismes moléculaires impliqués dans la programmation fœtale de l’HTA, sur plusieurs générations, ce qui pourrait aboutir à une meilleure prise en charge des patients nés prématurés ou avec une RCF, et de leurs descendants

Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences

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 with Hsd11b2, Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably for Gilz mRNA 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

SRY ‐negative 46,XX testicular/ovotesticular DSD: Long‐term outcomes and early blockade of gonadotropic axis

International audienceObjective: SRY-negative 46,XX testicular and ovotesticular disorders/differences of sex development (T/OTDSD) represent a very rare and unique DSD condition where testicular tissue develops in the absence of a Y chromosome. To date, very few studies have described the phenotype, clinical and surgical management and long-term outcomes of these patients. Particularly, early blockade of the gonadotropic axis in patients raised in the female gender to minimize postnatal androgenization has never been reported.Design: Retrospective description of sixteen 46,XX T/OTDSD patients.Results: Sixteen 46,XX SRY-negative T/OTDSD were included. Most (12/16) were diagnosed in the neonatal period. Sex of rearing was male for six patients and female for ten, while the clinical presentation varied, with an external masculinization score from 1 to 10. Five patients raised as girl were successfully treated with GnRH analog to avoid virilization during minipuberty. Ovotestes/testes were found bilaterally for 54% of the patients and unilaterally for the others (with a contralateral ovary). Gonadal surgery preserved appropriate tissue in the majority of cases. Spontaneous puberty occurred in two girls and one boy, while two boys required hormonal induction of puberty. One of the girls conceived spontaneously and had an uneventful pregnancy. DNA analyses (SNP-array, next-generation sequencing and whole-exome sequencing) were performed. A heterozygous frameshit mutation in the NR2F2 gene was identified in one patient.Conclusions: This study presents a population of patients with 46,XX SRY-negative T/OTDSD. Early blockade of gonadotropic axis appears efficient to reduce and avoid further androgenization in patients raised as girls

Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up?

International audienceOBJECTIVE: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development.METHODS: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France.RESULTS: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% ( = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels).CONCLUSION: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.</p

Référentiel de la Société francophone du diabète (SFD) : vaccination chez la personne diabétique

International audienceObjective Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. Methods Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. Results Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. −2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% ( n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). Conclusion This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies