The last decade has witnessed tremendous progress in the understanding of the mineralocorticoid receptor (MR), its molecular mechanism of action, and its implications for physiology and pathophysiology. After the initial cloning of MR, and identification of its gene structure and promoters, it now appears as a major actor in protein-protein interaction networks. The role of transcriptional coregulators and the determinants of mineralocorticoid selectivity have been elucidated.Targeted oncogenesis and transgenic mouse models have identified unexpected sites of MR expression and novel roles for MR in non-epithelial tissues. These experimental approaches have contributed to the generation of new cell lines for the characterization of aldosterone signaling pathways, and have also facilitated a better understanding of MR physiology in the heart, vasculature, brain and adipose tissues. This review describes the structure, molecular mechanism of action and transcriptional regulation mediated by MR, emphasizing the most recent developments at the cellular and molecular level. Finally, through insights obtained from mouse models and human disease, its role in physiology and pathophysiology will be reviewed. Future investigations of MR biology should lead to new therapeutic strategies, modulating cell-specific actions in the management of cardiovascular disease, neuroprotection, mineralocorticoid resistance, and metabolic disorders. Received July 20th, 2007; Accepted Novemeber 2nd, 2007; Published Novemeber 30th, 2007 | Abbreviations: 11β-HSD2: 11β-hydroxysteroid dehydrogenase 2; ACE: angiotensin converting enzyme; ACTH: adrenocorticotrophic hormone; ADAMTS1: a disintegrin and metalloproteinase with thrombospondin-like motifs 1; adPHA1: autosomal dominant pseudohypoaldosteronism type 1; AF1: activation function 1; AF2: activation function 2; ANF: atrial natriuretic factor; AR: androgen receptor; ASC2: activating signal cointegrator 2; BMP2: bone morphogenetic protein 2; CBP: CREB binding protein; CHIF: channel-inducing factor; CNS: central nervous system; DAXX: death-associated protein 6; DBD: DNA binding domain; EGF-R: epidermal growth factor receptor; Egr-1: early growth response gene-1; ELL: eleven-nineteen lysine-rich leukemia; ENaC: epithelial sodium channel; ERK: extracellular signal-regulated kinase; ET-1: endothelin-1; FAF1: Fas associated factor 1; FLASH: FLICE associated huge; G6PD: glucose-6-phosphate dehydrogenase; GILZ: glucocorticoid-induced leucine zipper protein; GR: glucocorticoid receptor; GRE: glucocorticoid responsive element; HAS2: hyaluronic acid synthase 2; HDAC: histone deacetylase; hMR: human mineralocorticoid receptor; HRE: hormone responsive element; hsp: heat shock protein; KS-WNK1: kidney specific with no lysine [K] kinase 1; LBD: ligand binding domain; LXRβ: liver X receptor β; MAPK: mitogen-activated protein kinase; MDM2: murine double minute gene 2; MR: mineralocorticoid receptor; MRE: mineralocorticoid responsive element; NAD: nicotinamide adenine dinucleotide; NCoR: nuclear receptor core...

The human leukocyte antigen (HLA)-A2-restricted zinc transporter (ZnT)8186–194 and other islet epitopes elicit interferon-γ secretion by CD8+ T cells preferentially in type 1 diabetes (T1D) patients compared with controls. Here, we show that clonal ZnT8186–194-reactive CD8+ T cells express private T-cell receptors and display equivalent functional properties in T1D and healthy subjects. Ex-vivo analyses further revealed that CD8+ T cells reactive to ZnT8186–194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186–194-reactive CD8+ T cells with a more antigen-experienced phenotype were detected in children vs. adults, irrespective of disease status. Moreover, some ZnT8186–194-reactive CD8+ T-cell clonotypes were found to cross-recognize a Bacteroides stercoris mimotope. While ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expressions levels of islet antigens did not modulate the peripheral frequency of their cognate CD8+ T cells. In contrast, ZnT8186–194-reactive cells were enriched in the pancreata of T1D donors vs. non-diabetic and type 2 diabetic controls. Thus, islet-reactive CD8+ T cells circulate in most individuals, but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T-cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a pro-inflammatory islet microenvironment.

ABSTRACT:In the neonatal period, the human kidney is characterized by an impaired ability to regulate water and sodium homeostasis, resembling partial aldosterone resistance. The aim of our study was to assess this hormonal insensitivity in newborn infants and to determine its relationship with neonatal sodium handling. We conducted a prospective study in 48 healthy newborns and their mothers. Aldosterone, renin, and electrolyte concentrations were measured in umbilical cords and in maternal plasma. Urinary aldosterone concentrations and sodium excretion were determined at urination within 24 h after birth. A significant difference was observed between aldosterone and renin levels in newborn infants compared with their mothers (817 Ϯ 73 versus 575 Ϯ 55 pg/mL and 79 Ϯ 10 versus 15 Ϯ 2 pg/mL, respectively, p Ͻ 0.001). This hyperactivation of the renin-angiotensin-aldosterone system was associated with hyponatremia and hyperkalemia in the newborn infants, and high urinary sodium loss, consistent with a partial aldosterone resistance at birth. Unlike plasma aldosterone, urinary aldosterone concentration was found highly correlated with plasma potassium concentrations, thus representing the best index for accurate evaluation of mineralocorticoid sensitivity. Our study represents a comprehensive characterization of the renin-aldosterone axis in newborn infants and provides evidence for physiologic partial aldosterone resistance in the neonatal period. (Pediatr Res 66: 323-328, 2009) T he human kidney displays a tubular immaturity at birth, with sodium waste, responsible for a negative sodium balance, and an impaired ability to reabsorb water (1), which is aggravated under circumstances such as prematurity, pyelonephritis, and gastroenteritis (2). This inability to maintain homeostatic functions is a major problem encountered by pediatricians, most notably in preterm infants. Indeed, the challenge is to find a balance between the lethal risk of dehydration and the associated morbidity of excessive hydromineral supplementation, contributing to severe complications such as intraventricular hemorrhage and bronchopulmonary dysplasia (3). A better understanding of water and sodium regulation in the neonatal period is a prerequisite to propose new therapeutic strategies for the management of preterm infants.Sodium reabsorption is mainly controlled by aldosterone, a steroid hormone synthesized in the zona glomerulosa of the adrenal gland, secondary to renin stimulation via angiotensin II and to potassium stimulation (4). In the distal nephron, aldosterone, by binding to its receptor, the mineralocorticoid receptor, a transcription factor (5), tightly regulates the expression and the activity of several transport proteins implicated in sodium, potassium, and water homeostasis, as the alpha subunit of the epithelial sodium channel (6), the Na-KATPase (7), and the aquaporin 2 (8). A possible role of a partial and transient tubular unresponsiveness to this hormone has been suggested to account for sodium waste in neonates (9,10)....

Loss of function of cyclin E1 or E2, important regulators of the mitotic cell cycle, yields viable mice, but E2-deficient males display reduced fertility. To elucidate the role of E-type cyclins during spermatogenesis, we characterized their expression patterns and produced additional deletions of Ccne1 and Ccne2 alleles in the germline, revealing unexpected meiotic functions. While Ccne2 mRNA and protein are abundantly expressed in spermatocytes, Ccne1 mRNA is present but its protein is detected only at low levels. However, abundant levels of cyclin E1 protein are detected in spermatocytes deficient in cyclin E2 protein. Additional depletion of E-type cyclins in the germline resulted in increasingly enhanced spermatogenic abnormalities and corresponding decreased fertility and loss of germ cells by apoptosis. Profound meiotic defects were observed in spermatocytes, including abnormal pairing and synapsis of homologous chromosomes, heterologous chromosome associations, unrepaired double-strand DNA breaks, disruptions in telomeric structure and defects in cyclin-dependent-kinase 2 localization. These results highlight a new role for E-type cyclins as important regulators of male meiosis.

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 11beta-hydroxysteroid dehydrogenase type 2 and the epithelial sodium channel alpha-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.

Context: Gender assignment followed by surgery and hormonal therapy is a difficult decision in the management of 45,X/46,XY patients with abnormal external genitalia at birth considering the paucity of studies evaluating pubertal development and fertility outcome, most notably for patients raised as boys. Objective: The purpose of this study was to describe the pubertal course of 20 45,X/46,XY patients born with ambiguous genitalia and raised as boys. Methods: This is a multicenter retrospective study. Results: Mean age at study was 25.6G2.4 years. Eighty-five percent of the patients presented a 'classical' mixed gonadal dysgenetic phenotype at birth. Puberty was initially spontaneous in all but three boys, although in six other patients, testosterone therapy was subsequently necessary for completion of puberty. Sixty-seven percent of the remaining patients presented signs of declined testicular function at the end of puberty (increased levels of FSH and low levels of testosterone and/or inhibin B). Moreover, an abnormal structure of the Y chromosome, known to alter fertility, was found in 10 out of 16 (63%) patients. Two patients developed testicular cancer. Half of the patients have adult penile length of !80 mm. Mean adult height is 156.9G2 cm, regardless of GH treatment. Conclusions: In summary, 45,X/46,XY children born with ambiguous genitalia and raised as boys have an altered pubertal course and impaired fertility associated with adult short stature, which should, therefore, be taken into consideration for the management of these patients.

Functional ARs are essential for TT-mediated AMH repression in SC.

Purpose: XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. Methods: We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS. Results: Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10 −10). Five variants are de novo (P value = 1.5 × 10 −5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. Conclusion: DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.