Say Viengchareun

Eric Pussard

Mireille Castanet

Laurent M Sachs

Pascal Vu

Marc Boileau

Laetitia Lombès

Martinerie

Thi An Vu

Pascal Boileau

Marc Lombès

MD Laetitia Martinerie
email: laetitia.martinerie@aphp.fr

The invention of aldosterone, how the past resurfaces in pediatric endocrinology

Keywords: Aldosterone, mineralocorticoid receptor, neonates, human, amphibian, fish

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Introduction

Sodium and water homeostasis are finely regulated by the mineralocorticoid signaling pathway, notably in the distal nephron in mammals. However, this equilibrium is challenged at birth by the transition from intrauterine to extrauterine life. Accumulating evidence suggests that aldosterone may be one of the key regulators for this transition. This review will emphasize the regulation and role of the mineralocorticoid signaling pathway (mainly aldosterone and its receptor, the mineralocorticoid receptor), throughout fetal and neonatal development, in the light of evolution.

Sodium and Water Homeostasis and Special Features in Full-term and Preterm Newborns

Sodium and water homeostasis constitute the physiological processes regulating the stability of plasma osmolarity and plasma volume. Water is divided in the body into three compartments: the intracellular compartment, and the interstitial and plasma compartments that both form the extracellular compartment. The body water content depends on the water stock, but its distribution among the different compartments relies mainly on sodium balance. In humans, sodium balance is regulated by two variables: food inputs, and outputs (renal in majority, and extrarenal in minority, under physiological conditions). The efficiency of renal control of sodium and water balance is based on an equilibrium between the filtered sodium flow (dependent on serum sodium and glomerular filtration rate) and tubular reabsorption of sodium [START_REF] Devuyst | Salt wasting and blood pressure[END_REF]. The latter is made possible by the joint and coordinated intervention of the different segments of the nephron, contributing to the reabsorption of 99% of the ultrafiltered sodium. The distal parts of the nephron (distal convoluted tubule, connecting duct and collecting duct) are involved in the fine regulation of sodium balance [START_REF] Palmer | Integrated Control of Na Transport along the Nephron[END_REF]. The effectors of this regulation act in response to stimulation of baroreceptors and voloreceptors; these are various neuroendocrine systems including the renin-angiotensinaldosterone system (RAAS), the atrial natriuretic factor, vegetative innervation, or the prostaglandin system. Segments of the nephron expressing the mineralocorticoid receptor (MR) are grouped together under the term Aldosterone Sensitive Distal Nephron (ASDN). The epithelium of the collecting duct is made up of tight intercellular junctions (desmosomes) preventing any extracellular transport. Transcellular sodium reabsorption therefore involves two main transporters: the Epithelial Na + Channel (ENaC) and the Na + /K + -ATPase pump. In addition, the principal cells of the collecting duct are also the site of transepithelial water reabsorption thanks to the osmotic force induced by sodium transport. This water reabsorption is mostly ensured by the aquaporic channels: AQP2, expression of which is located at the apical membrane, is induced by vasopressin and also regulated by aldosterone [START_REF] Hasler | Dual influence of aldosterone on AQP2 expression in cultured renal collecting duct principal cells[END_REF] while AQP3 and AQP4 are constitutively expressed at the basolateral membrane. The collecting duct therefore appears to be the site of the final modulation of renal sodium and water reabsorption.

In utero, sodium and water homeostasis are initially regulated in the fetus by the placenta.

Kidneys only play an ancillary role, since the absence of a kidney is compatible with a live born infant at full-term (anephric newborn) [START_REF] Gunn | Outcome after antenatal diagnosis of upper urinary tract dilatation by ultrasonography[END_REF]. Glomerular filtration and emission of the first urine begin at the 10 th gestational week (GW) contributing to the production of amniotic fluid. The amount of amniotic fluid increases from 25 ml at 10 GW to 400 ml at 20 GW, with a composition similar to that of the fetal plasma. Indeed, prior to skin keratinization, water and solutes diffuse freely between spaces, in a bidirectional manner. The amniotic fluid then serves as a physiological buffer and corresponds to an extension of the extracellular environment of the fetus. Fetal keratinization begins around 14 GW with a phase of follicular keratinization, then continues with a phase of interfollicular keratinization which usually ends at the 25 th GW. After this phase of keratinization, the volume and composition of the amniotic fluid become dependent on several levels of regulation (renal production, swallowing of the fetus, oral, esophageal and pulmonary fluids of the fetus, inter and transmembrane transfers), and are then submitted to active exchanges between the different compartments [START_REF] Underwood | Amniotic fluid: not just fetal urine anymore[END_REF]. Thus, along with the development of the various functions of the kidneys, composition of the amniotic fluid evolves. Sodium and chlorine concentrations decrease from the second trimester of pregnancy, while urea and creatinine concentrations increase. The overall osmolality of amniotic fluid decreases [START_REF] Underwood | Amniotic fluid: not just fetal urine anymore[END_REF]. Around 36 GW, nephrogenesis (formation of new nephrons) is complete, and the kidneys, although still immature, can take over the regulation of sodium and water balance in the fetus.

At birth and in the postnatal period, renal function must adapt to the delicate task of establishing an effective purification function while ensuring the fluid-electrolyte balance. The immaturity of the main renal functions (glomerular and tubular) in the newborn, the disruption of the composition of the internal environment by the physiological changes of transition between the intrauterine aquatic environment and the extrauterine terrestrial environment, and the need to adapt to the requirements of rapid growth, make this phase of adaptation all the more complex. Growth requires the establishment of a positive hydro-electrolyte balance, with inputs greater than outputs. As part of the adjustment to extrauterine life, other important changes are added during the neonatal period. The physiological weight loss observed during the neonatal period (usually up to 5-10% of the body weight) occurs mainly to the detriment of the extracellular compartment and more particularly the interstitial compartment (the vascular compartment remaining stable, of the order of 5% from birth, as in adults). The urine output of full-term newborns is between 1 and 3 ml/kg/h. The reduction of extracellular volume may reach 15% of body weight in premature infants and is associated with a urine output of up to 7 ml/kg/h [START_REF] Lindower | Water balance in the fetus and neonate[END_REF][START_REF] Suarez-Rivera | Fluid and Electrolyte Disorders in the Newborn: Sodium and Potassium[END_REF]. Glomerular filtration increases sharply during the first hours of life, however, remains low (20 ml/min/1.73m 2 ). It is multiplied by 2 on the 15 th day of life, then increases more gradually to reach levels close to that of adults at the age of 1 year. The glomerular filtration rate is even lower in very premature infants, around 10 ml/min/1.73 m 2 at birth [START_REF] Bockenhauer | Electrolyte disorders[END_REF]. This partially explains the slow elimination of maternal plasma creatinine levels, which takes only a few days in the full-term newborn, and can reach several weeks in the very premature infant (van den [START_REF] Van Den Anker | Assessment of glomerular filtration rate in preterm infants by serum creatinine: comparison with inulin clearance[END_REF]. The mechanism of concentration/dilution of urine is essential to regulate water balance. This mainly relies on the action of vasopressin or antidiuretic hormone. In newborns, urine osmolality is lower, in the order of 600 mOsm/kg, or even 500 mOsm/kg in premature babies. The capacity to concentrate urine increases gradually and reaches adult levels around the age of 1 year [START_REF] Suarez-Rivera | Fluid and Electrolyte Disorders in the Newborn: Sodium and Potassium[END_REF]. Conversely, the power of urine dilution is acquired in utero, and does not differ between premature infants, full-term newborns and adults. Under normal physiological conditions, the kidneys of the full-term newborns must excrete the fluid overload acquired during fetal life [START_REF] Lindower | Water balance in the fetus and neonate[END_REF].

Therefore, the ability to concentrate urine is not necessary at birth. However, in premature infants, whose fluid overload is greater and the power of urine concentration weaker, the risk of hydro-electrolyte disorders becomes significant [START_REF] Bockenhauer | Electrolyte disorders[END_REF][START_REF] Suarez-Rivera | Fluid and Electrolyte Disorders in the Newborn: Sodium and Potassium[END_REF].

Renal control of sodium excretion is essential for maintaining blood volume and a positive sodium balance, crucial for normal growth. The fraction of excreted sodium is high at birth but decreases rapidly in full-term newborns and reaches less than 1% [START_REF] Suarez-Rivera | Fluid and Electrolyte Disorders in the Newborn: Sodium and Potassium[END_REF]. In premature infants, this adaptation takes place more slowly, over 2 to 3 weeks, especially before 34 GW, where the fraction of excreted sodium can reach 3 to 5% and often requires systematic sodium supplementation [START_REF] Suarez-Rivera | Fluid and Electrolyte Disorders in the Newborn: Sodium and Potassium[END_REF]. The fullterm newborn retains about 30% of the sodium ingested, however cannot excrete excess sodium or water load. This ability is not acquired until the end of the first year of life [START_REF] Zoetis | Species comparison of anatomical and functional renal development[END_REF]. All of these maturation processes of renal function are integrated with the development of the different structures of the kidney [START_REF] Zoetis | Species comparison of anatomical and functional renal development[END_REF] and the progressive expression of the different players (hormone receptors, ion channels and transporters) of the regulation of sodium and water balance, in particular of the mineralocorticoid signaling pathway.

The Mineralocorticoid Signaling Pathway

The first step in the activation of the mineralocorticoid signaling pathway is characterized by the biosynthesis and secretion of the steroid hormone aldosterone, which is the predominant mineralocorticoid hormone in mammals. This hormone is synthesized in the zona glomerulosa (ZG) of the adrenal cortex.

Aldosterone Biosynthesis, Secretion, and Regulation

The pathway of human aldosterone biosynthesis by the ZG is now well understood. The ZG is the outermost layer of the adrenal cortex, lying just beneath the fibrous capsule and composed of clustered cells that uniquely express aldosterone synthase (CYP11B2), the steroidogenic enzyme encoded by the CYP11B2 gene that performs the final stages of aldosterone production.

Beneath the ZG, lies the zona fasciculata (ZF), and, underneath, the zona reticularis (ZR), which produces glucocorticoids and adrenal androgens, respectively [START_REF] Seccia | The Biology of Normal Zona Glomerulosa and Aldosterone-Producing Adenoma: Pathological Implications[END_REF].

The first step in steroidogenesis takes place within mitochondria that contains very little cholesterol. The steroidogenic acute regulatory protein, StAR (encoded by the STAR gene) ensures cholesterol import from the outer to the inner mitochondrial membrane. This mitochondrial translocation is the rate-limiting step in steroidogenesis. Then, the mitochondrial enzyme, cytochrome P450scc (encoded by the CYP11A1 gene) cleaves cholesterol sidechain to produce pregnenolone. Subsequent conversion of pregnenolone to progesterone is catalyzed by the type 2 3β-hydroxysteroid dehydrogenase/dΔ5-Δ4 isomerase, encoded by the HSD3B2 gene and located in the membrane of the endoplasmic reticulum. As the adrenal ZG does not express P450c17, progesterone is 21-hydroxylated into 11-deoxycorticosterone (DOC) by the microsomal P450c21 encoded by the CYP21A2 gene. The restricted expression of aldosterone synthase (P450c11AS encoded by the CYP11B2 gene, located at 8q22 in humans, and comprising 9 exons and over 7000 base pairs [START_REF] Bassett | The regulation of aldosterone synthase expression[END_REF] ensures zonal control of aldosterone secretion in ZG. CYP11B2 gene locates in tandem with the highly homologous CYP11B1 gene, which encodes the 11β-hydroxylase enzyme essential to cortisol synthesis in ZF. Nevertheless, CYP11B1 gene and CYP11B2 are never commonly coexpressed and P450c11AS sequentially catalyzes 11-hydroxylase, 18-hydroxylase and 18-methyl oxidase activities in ZG, yielding successively to corticosterone, 18-hydroxycorticosterone and finally aldosterone [START_REF] Miller | The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders[END_REF].

As the adrenal ZG has no capacity to store aldosterone once it is produced, the regulation of the secretion is inextricably linked to transcriptional activation as well as posttranscriptional modification of steroidogenic enzymes. Acute aldosterone production is controlled by the early regulatory step of cholesterol uptake and conversion to pregnenolone that is mediated by increased expression and phosphorylation of StAR. A late regulatory step controlling the expression of biosynthesis enzymes, particularly CYP11B2, regulates chronic aldosterone production. Aldosterone biosynthesis in the ZG is physiologically regulated by angiotensin II (Ang II), potassium (K + ), and at a lesser extent by the adrenocorticotropic hormone (ACTH).

Membrane depolarization and increase in intracellular calcium levels are the most important determinants of aldosterone secretion (Figure 1). The renin-angiotensin-aldosterone system (RAAS) is initiated by various stimuli such as increased sympathetic activity, reduced perfusion pressure in the renal afferent arterioles or decreased sodium content facing the macula densa of the renal distal tubules that release renin from juxtaglomerular cells. Afterward, renin converts angiotensinogen to angiotensin I, which is subsequently cleaved by Angiotensin Converting Enzyme (ACE) to form the octapeptide Ang II. Binding of Ang II to its AT1 receptor activates phospholipase C, and, thus, triggers an InsP3-dependent release of calcium from intracellular stores. A sustained aldosterone secretion induced by Ang II requires additional calcium entry from membrane calcium channels. The raised cytoplasmic calcium concentration in the ZG activates calcium/calmodulin-dependent protein kinases (CaMKs), which increase expression and phosphorylation of transcription factors such as Nur-related factor 1 (Nurr1), nerve growth factor-induced clone B (NGFIB), Activating transcription factor 1 (ATF1), and CAMP responsive element binding protein 1 (CREB1). These transcription factors in turn activate promoter sites of CYP11B2 and StAR transcription and increase aldosterone. The higher demand for cholesterol requires its uptake from plasma lipoproteins. Ang II increases the expression of LDL and HDL receptors, which improves cholesterol availability for steroidogenesis. Ang II also activates the cellular hormone-sensitive lipase to release cholesterol stored in esterified form in lipid droplets [START_REF] Mackenzie | Regulation of Aldosterone Secretion[END_REF]. Circulating potassium is also one of the major regulators of aldosterone secretion in ZG cells. Adrenal glomerulosa cells exhibit a high background potassium membrane conductance. Small increases in extracellular potassium depolarize the glomerulosa cells, increasing calcium influx through voltage-gated calcium channels that stimulates CYP11B2 and StAR transcription [START_REF] Hattangady | Acute and chronic regulation of aldosterone production[END_REF]. Therefore, multiple potassium and calcium channels regulate aldosterone secretion. ZG potassium channels as well as Na + -K + -ATPase control the repolarization of the cell membrane following calcium influx; any alteration of cell repolarization extends the time of calcium channels opening and therefore lengthens the duration of aldosterone secretion. Several mutations affecting ion channels and pumps have been reported to be associated with hormone overproduction in autonomous aldosteroneproducing adenomas [START_REF] Beuschlein | Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension[END_REF][START_REF] Choi | K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension[END_REF][START_REF] Fernandes-Rosa | A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism[END_REF][START_REF] Nakamura | Aldosterone biosynthesis in the human adrenal cortex and associated disorders[END_REF][START_REF] Scholl | CLCN2 chloride channel mutations in familial hyperaldosteronism type II[END_REF][START_REF] Scholl | Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism[END_REF][START_REF] Scholl | Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism[END_REF][START_REF] Zennaro | Pathogenesis and treatment of primary aldosteronism[END_REF]Zennaro et al., , 2017)).

ACTH only stimulates aldosterone secretion acutely and transiently, but to a lesser extent than Ang II and K + . ACTH binds to the transmembrane receptor melanocortin receptor 2 expressed both in ZG and ZF cells and exerts its downstream effects by activating adenylate cyclase, thus stimulating StAR expression [START_REF] Betancourt-Calle | Differential effects of agonists of aldosterone secretion on steroidogenic acute regulatory phosphorylation[END_REF]. Aldosterone production is also regulated through a paracrine mechanism by bioactive compounds (leptin, serotonin, catecholamines, atrial natriuretic peptide, endothelin, nitric oxide, neuropeptide substance P) released by various cells such as adipocytes, mast cells, chromaffin cells or nerve ending located in the vicinity of adrenocortical ZG cells [START_REF] Lefebvre | Paracrine Regulation of Aldosterone Secretion in Physiological and Pathophysiological Conditions[END_REF][START_REF] Wils | The neuropeptide substance P regulates aldosterone secretion in human adrenals[END_REF]. Finally, some studies have shown that numerous miRNAs regulate aldosterone production though posttranscriptional regulation of CYP11B2 or StAR expressions [START_REF] Robertson | Regulation of Corticosteroidogenic Genes by MicroRNAs[END_REF].

The Mineralocorticoid Receptor

Gene structure and functional domains

The genomic effects of aldosterone are mediated by the Mineralocorticoid Receptor (MR), a nuclear receptor acting as a transcription factor capable of modulating expression of target genes responsible for physiological effects of aldosterone [START_REF] Viengchareun | The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology[END_REF]. The NR3C2 gene, encoding the human MR, extends over nearly 450 kb and is located at locus 4q31.1-4q31.2 [START_REF] Fan | The human mineralocorticoid receptor gene (MLR) is located on chromosome 4 at q31.2[END_REF][START_REF] Morrison | Regional chromosomal assignment of the human mineralocorticoid receptor gene to 4q31.1[END_REF]. The hMR gene presents with 10 exons and 8 introns: the first two exons, 1 and 1, are not translated and are spliced alternatively onto the common exon 2, generating two messenger isoforms (hMR  and hMR ), which encode the same 984 amino-acids protein (~107 kDa) [START_REF] Zennaro | Human mineralocorticoid receptor genomic structure and identification of expressed isoforms[END_REF]. MR protein is organized into four distinct structural domains, including the N-terminal domain (NTD), the DNA binding domain (DBD), the hinge region and the ligand binding domain (LBD).

MR Expression in Epithelial and Non-epithelial Tissues

MR expression was first described in epithelial tissues, in which MR and aldosterone stimulate sodium reabsorption and excretion of potassium [START_REF] Bonvalet | Regulation of sodium transport by steroid hormones[END_REF][START_REF] Marver | Renal aldosterone receptors: studies with (3H)aldosterone and the anti-mineralocorticoid (3H)spirolactone (SC-26304)[END_REF]. Its expression was demonstrated in the kidney, first in the distal convoluted tubules and cortical collecting ducts [START_REF] Krozowski | Immunolocalization of renal mineralocorticoid receptors with an antiserum against a peptide deduced from the complementary deoxyribonucleic acid sequence[END_REF][START_REF] Lombès | Immunohistochemical localization of renal mineralocorticoid receptor by using an antiidiotypic antibody that is an internal image of aldosterone[END_REF] and later, in the mesangial cells [START_REF] Miyata | Aldosterone stimulates reactive oxygen species production through activation of NADPH oxidase in rat mesangial cells[END_REF][START_REF] Nishiyama | Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability[END_REF] and podocytes of the glomeruli [START_REF] Shibata | Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1[END_REF]. In parallel, MR expression was detected in the distal colon of rat [START_REF] Pressley | Glucocorticoid and mineralocorticoid receptors in gut mucosa[END_REF], human [START_REF] Lombes | Aldosterone binding in the human colon carcinoma cell line HT29: correlation with cell differentiation[END_REF] and chick [START_REF] Rafestin-Oblin | Mineralocorticosteroid receptor of the chick intestine. Oligomeric structure and transformation[END_REF], and in airway epithelia from bronchiole to trachea [START_REF] Krozowski | Mineralocorticoid receptors in the rat lung[END_REF], in the salivary [START_REF] Funder | Specific aldosterone binding in rat kidney and parotid[END_REF] and sweat glands [START_REF] Kenouch | Human skin as target for aldosterone: coexpression of mineralocorticoid receptors and 11 beta-hydroxysteroid dehydrogenase[END_REF], in the liver [START_REF] Duval | The binding of tritiated aldosterone in the rat liver cytosol[END_REF] and in the inner ear [START_REF] Furuta | Mineralocorticoid type I receptor in the rat cochlea: mRNA identification by polymerase chain reaction (PCR) and in situ hybridization[END_REF][START_REF] Nevoux | Glucocorticoids stimulate endolymphatic water reabsorption in inner ear through aquaporin 3 regulation[END_REF][START_REF] Pitovski | High affinity aldosterone binding sites (type I receptors) in the mammalian inner ear[END_REF][START_REF] Teixeira | Functional IsK/KvLQT1 potassium channel in a new corticosteroid-sensitive cell line derived from the inner ear[END_REF]. Subsequently, MR expression was intriguingly detected in non-epithelial tissues. Indeed, specific aldosterone-binding sites were revealed in mononuclear leukocytes [START_REF] Armanini | Characterization of aldosterone binding sites in circulating human mononuclear leukocytes[END_REF] and macrophages [START_REF] Lim | Glucocorticoids exert opposing effects on macrophage function dependent on their concentration[END_REF]. Thereafter, MR expression was detected in the hippocampus, which is a brain structure involved in many cognitive processes [START_REF] Herman | Localization and regulation of glucocorticoid and mineralocorticoid receptor messenger RNAs in the hippocampal formation of the rat[END_REF][START_REF] Van Eekelen | Distribution of the mineralocorticoid and the glucocorticoid receptor mRNAs in the rat hippocampus[END_REF] suggesting that aldosterone and MR may be involved in memory processes [START_REF] Pavlides | Effects of mineralocorticoid and glucocorticoid receptors on longterm potentiation in the CA3 hippocampal field[END_REF]. In 1992, the discovery of MR expression in the heart and in the large vessels further broadened the field of investigation into the mechanism of action of aldosterone and its receptor and allowed research to be directed towards previously unsuspected pharmacological and therapeutic perspectives, particularly in the field of cardiology. Immunohistochemistry showed that MR was clearly expressed in myocytes and in endothelial cells of the atria and ventricles in rabbits. In large vessels, MR was found in the aorta and pulmonary artery, particularly in endothelial cells and vascular smooth muscle cells [START_REF] Lombès | Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor[END_REF]. Interestingly, MR expression was also demonstrated in skin, a stratified epithelium in which no ion transport had been clearly established even though amphibian skin had long been known as the site of ion transport [START_REF] Kenouch | Human skin as target for aldosterone: coexpression of mineralocorticoid receptors and 11 beta-hydroxysteroid dehydrogenase[END_REF][START_REF] Sainte Marie | Targeted skin overexpression of the mineralocorticoid receptor in mice causes epidermal atrophy, premature skin barrier formation, eye abnormalities, and alopecia[END_REF]. More intriguingly, MR expression was detected in adipose tissues, in which MR was shown to play a pivotal role in white adipocyte differentiation [START_REF] Caprio | Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis[END_REF][START_REF] Rondinone | Aldosterone stimulated differentiation of mouse 3T3-L1 cells into adipocytes[END_REF]. In addition, our group identified the brown adipose tissue as a novel target for aldosterone action [START_REF] Zennaro | Hibernoma development in transgenic mice identifies brown adipose tissue as a novel target of aldosterone action[END_REF] and demonstrated that aldosterone is capable of inducing differentiation of brown adipocytes [START_REF] Penfornis | The mineralocorticoid receptor mediates aldosterone-induced differentiation of T37i cells into brown adipocytes[END_REF] and exerts a control on energy balance. This list of MR expression in tissues is far from being exhaustive. Indeed, MR is also expressed in several structures of the eyeball such as the retina, the pigmentary epithelium, the ciliary bodies of the iris and the cornea [START_REF] Mirshahi | Immunochemical demonstration of the mineralocorticoid receptor in ocular tissues[END_REF][START_REF] Schwartz | Mineralocorticoid receptors in the rabbit iris-ciliary body[END_REF]. MR is also expressed in placenta [START_REF] Hirasawa | 11Betahydroxysteroid dehydrogenase type II and mineralocorticoid receptor in human placenta[END_REF], uterus, ovaries and testes, spleen and smooth muscle (Le Menuet et al., 2000a). Thus, this broad tissue expression of MR strongly suggests that MR exerts functions other than those previously described in polarized epithelial tissues.

Mechanism of MR Action in a Renal Polarized Epithelial Cell

In a typical polarized epithelial principal cell of the distal nephron, aldosterone enters cells by passive diffusion and binds to the MR (Figure 2). This latter is exclusively located in the cytoplasm in the absence of its ligand and is complexed with various chaperon proteins (hsp70, hsp90, Cyp40, FKBP52). Then, the binding of aldosterone to MR induces dissociation of these chaperon proteins and conformational changes of the receptor. After translocation to the nuclear compartment, the hormone-receptor complex binds mostly as homodimers to specific DNA sequences, identified as Mineralocorticoid Response Elements (MREs), which are in the regulatory regions of aldosterone-sensitive genes. The consensus sequence of these MREs corresponds to a 15-nucleotide-sequence AGaACAgxaTGTtCt consisting of partial palindromic motif as identified by Chromatin Immunoprecipitation assays followed by DNA sequencing (ChIP-Seq) [START_REF] Le Billan | Cistrome of the aldosterone-activated mineralocorticoid receptor in human renal cells[END_REF]. Thereafter, MR interacts, in a cyclic, sequential and/or combinatorial manner [START_REF] Le Billan | Corticosteroid receptors adopt distinct cyclical transcriptional signatures[END_REF], with several transcriptional coregulators and some basal transcription factors or components of the machinery to enhance transcriptional activation (initiation and elongation) and to facilitate chromatin remodeling involving histone acetylation/methylation [START_REF] Le Billan | Cistrome of the aldosterone-activated mineralocorticoid receptor in human renal cells[END_REF]. In epithelial tissues (kidney and colon), MR stimulates expression of ionic transporters: the Epithelial Na + Channel (ENaC) and the basolateral Na + ,K + -ATPase pump, which are involved in the unidirectional transepithelial sodium transport from the lumen to the interstitium. The Serum and glucocorticoid-regulated kinase 1 (sgk1) is the most studied aldosterone-stimulated gene in epithelial tissues, which phosphorylates the ubiquitin ligase Nedd4-2, which in turn controls the retrieval of the subunits of ENaC from the apical membrane of the cell. Several other target genes have been identified such as the Glucocorticoid-Induced Leucine Zipper protein (GILZ), the serine/threonine kinase KS-WNK1 (With No lysine K kinase), the N-myc Down-Regulated Gene 2 (NDRG2), or the small monomeric GTP-binding protein Kirsten Ras (Ki-Ras), which also seem to play pivotal roles during the early phase of aldosterone responses in the nephron [START_REF] Viengchareun | The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology[END_REF][START_REF] Laulhé | Sexual Dimorphism of Corticosteroid Signaling during Kidney Development[END_REF]. The PER1 gene has recently been identified as another aldosterone-target gene in the kidney [START_REF] Gumz | The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice[END_REF], suggesting that aldosterone may also regulate the

Regulation of MR expression

The NR3C2 gene expression is controlled by two alternative promoters [START_REF] Zennaro | Characterization of the human mineralocorticoid receptor gene 5'-regulatory region: evidence for differential hormonal regulation of two alternative promoters via nonclassical mechanisms[END_REF]. The proximal P1 promoter, corresponding to the 5′-flanking region of exon 1α of NR3C2 gene, is a relatively strong promoter that is transcriptionally active in all aldosterone target tissues, whereas the distal P2 promoter, flanking exon 1β of NR3C2 gene, is weaker and has a more restricted pattern of expression, notably in the central nervous system (Le Menuet et al., 2000b). Alternative transcription of these two 5′-untranslated exons (1α and 1) generates two mRNA isoforms, referred to as hMRα and hMRβ, which give rise to the same MR protein [START_REF] Zennaro | Human mineralocorticoid receptor genomic structure and identification of expressed isoforms[END_REF]. Interestingly, several other MR splice variants, lacking one (6 MR) or two exons (5,6 MR), have been identified so far and such splice variants seem to play major roles in modulating receptor function (Lema et al., 2017a;[START_REF] Zennaro | A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action[END_REF].

MR transcripts stability is also regulated at the posttranscriptional level. This is particularly relevant in the nephron where MR expression was recently shown to be modulated by large variations of extracellular tonicity, prevailing in the renal tubules [START_REF] Viengchareun | Osmotic stress regulates mineralocorticoid receptor expression in a novel aldosterone-sensitive cortical collecting duct cell line[END_REF]. Indeed, hypertonicity was shown to greatly decrease MR transcript levels by recruiting the RNA Binding Protein (RBP) Tis11b (tetradecanoyl phorbol acetate inducible sequence 11b), which physically interacts with MR transcript 3'-untranslated region (3′-UTR), thus modulating its mRNA turnover in response to osmotic stress [START_REF] Viengchareun | Hypertonicity compromises renal mineralocorticoid receptor signaling through Tis11bmediated post-transcriptional control[END_REF].

Conversely, MR transcript and protein levels were shown to increase under hypotonicity by recruiting HuR (Human antigen R), another RBP member of the Hu family. Under hypotonic stress, and rapidly exported from the nuclear compartment to the cytoplasm of renal cells where it interacts with MR 3′-UTR to stabilize and increase MR levels, thereby modulating MR signaling (Lema et al., 2017b). During this past decade, microRNAs (miRNAs) have also emerged as a new class of posttranscriptional regulators [START_REF] Bartel | MicroRNAs: genomics, biogenesis, mechanism, and function[END_REF][START_REF] Ozbaki-Yagan | Aldosterone-induced microRNAs act as feedback regulators of mineralocorticoid receptor signaling in kidney epithelia[END_REF]. Taken together, RNA Binding Protein and miRNAs seem to be of particular importance in the control of MR expression, presumably during the prenatal period and notably at birth, where renal MR expression is downregulated, accounting for the transient physiological renal resistance to aldosterone observed in the early neonatal period (Martinerie et al., 2009b).

Mineralocorticoid Selectivity Mechanism

In the absence of a mineralocorticoid selectivity mechanism, MR would be permanently occupied by glucocorticoid hormones since plasma concentration of these hormones is 100 to 1000 times higher than that of aldosterone in mammals, depending on the nychthemeral cycle of glucocorticoid hormones. This illicit occupation of the MR by glucocorticoid hormones is explained by the homology existing between the biochemical structure of aldosterone and cortisol and the high homology between the MR and the GR (Glucocorticoid Receptor). Indeed, the DBD and LBD of MR have, respectively, 94% and 57% identity with those of GR [START_REF] Arriza | Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor[END_REF]. Moreover, these two receptors bind to the same GRE sequences and in vitro experiments have shown that affinity of MR is identical for aldosterone and glucocorticoid hormones [START_REF] Arriza | Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor[END_REF][START_REF] Funder | Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated[END_REF]. The main mechanism responsible for mineralocorticoid selectivity relies on the 11-hydroxysteroid dehydrogenase type II (11HSD2), an enzyme belonging to the superfamily of short-chain alcohol dehydrogenases [START_REF] Edwards | Localisation of 11 beta-hydroxysteroid dehydrogenase--tissue specific protector of the mineralocorticoid receptor[END_REF][START_REF] Funder | Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated[END_REF][START_REF] Jörnvall | Shortchain dehydrogenases/reductases (SDR)[END_REF]. This enzyme has a high affinity for glucocorticoid hormones and oxidizes the alcohol function carried by carbon 11 of the glucocorticoid hormones into a ketone function, thus producing 11-dehydrogenated derivatives (cortisone for cortisol in humans and 11-dehydrocorticosterone for corticosterone in rodents) that have little or no affinity for MR, or even for GR [START_REF] Funder | Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated[END_REF]. In cells co-expressing MR and 11HSD2, the illicit occupation of the MR by glucocorticoid hormones is thus clearly limited by the action of this enzyme, allowing aldosterone to act selectively onto its receptor in order to specifically exert its biological effects on sodium reabsorption. Of note, mineralocorticoid selectivity is also ensured by an intrinsic property of the receptor since MR can discriminate between aldosterone and glucocorticoids because dissociation rates (k-1) are much faster for glucocorticoids than for aldosterone. Moreover, it has been shown that the aldosterone-MR complex adopts structural conformation somehow different from that of the glucocorticoid-MR complex, thereby allowing distinct interaction between the N-terminal domain and the LBD to occur. Thus, specific coactivators may be recruited resulting in a highly specific transcriptional response [START_REF] Farman | Multiple aspects of mineralocorticoid selectivity[END_REF]. Recently, it has also been demonstrated that specific cyclical and dynamic interaction of MR with DNA, as a function of the nature of the MR-bound ligand, is responsible for distinct transcriptional signatures [START_REF] Le Billan | Corticosteroid receptors adopt distinct cyclical transcriptional signatures[END_REF].

Ontogenesis of the Adrenal Gland and Mineralocorticoid Signaling Pathway Throughout Evolution

Ontogenesis of corticosteroid receptors during evolution

The corticosteroid signaling system in fish clearly differs from that of mammals [START_REF] Kiilerich | Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro[END_REF]. In fish, cortisol is the major corticosteroid while aldosterone seems to be lacking [START_REF] Jiang | Eel (Anguilla japonica) testis 11betahydroxylase gene is expressed in interrenal tissue and its product lacks aldosterone synthesizing activity[END_REF][START_REF] Prunet | Multiple corticosteroid receptors in fish: from old ideas to new concepts[END_REF]. Consequently, cortisol not only regulates energy metabolism but also hydromineral homeostasis notably during seawater and freshwater adaptation and via chloride cell function. Whether cortisol acts through the GR or MR remained a subject of debate for a long period of time. In the zebrafish, some authors demonstrated that cortisol could also activate the GR and functions as a mineralocorticoid by affecting epidermal ionocyte development and ion transport [START_REF] Cruz | Glucocorticoid receptor, but not mineralocorticoid receptor, mediates cortisol regulation of epidermal ionocyte development and ion transport in zebrafish (danio rerio)[END_REF][START_REF] Kumai | Cortisol regulates Na+ uptake in zebrafish, Danio rerio, larvae via the glucocorticoid receptor[END_REF]. Moreover, deoxycorticosterone (DOC), seems to be able to specifically bind and activate MR [START_REF] Sturm | 11deoxycorticosterone is a potent agonist of the rainbow trout (Oncorhynchus mykiss) mineralocorticoid receptor[END_REF].

Two GR isoforms (GR1 and GR2), probably raising from the 350 Million years ago whole genome duplication, have been described in many fishes while the MR seems to derive from the ancestral Corticosteroid Receptor (CR), expressed in the lamprey and hagfish [START_REF] Baker | Steroid receptors and vertebrate evolution[END_REF], however its role remains to be further clarified. Ontogenesis of MR and GR during evolution revealed that both receptor expressions appeared in the Chondrichthyes, including sharks and that they are also expressed in the teleost fish such as Holostei and Sturgeons. Aldosterone was first detected in the lungfish and remains detected in the subsequent vertebrates: frogs, salamanders, turtles, lizards, snakes, crocodiles, birds, and mammals (Figure 3).

Recently, progesterone was shown to be an MR agonist in a range of teleost fish [START_REF] Pippal | Characterization of the zebrafish (Danio rerio) mineralocorticoid receptor[END_REF]Baker and Katsu, 2017;[START_REF] Katsu | Evolution of human, chicken, alligator, frog, and zebrafish mineralocorticoid receptors: Allosteric influence on steroid specificity[END_REF][START_REF] Fuller | Structural determinants of activation of the mineralocorticoid receptor: an evolutionary perspective[END_REF]. This rather unexpected result could be explained by the demonstration that leucine substitution by serine or threonine at position 810 in helix-5 of the MR LBD enables contact with an alanine at position 773 in helix-3, suggesting that helix-3/helix-5 interaction is critical for ligand-dependent MR activation [START_REF] Geller | Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy[END_REF][START_REF] Zhang | A critical role of helix 3-helix 5 interaction in steroid hormone receptor function[END_REF][START_REF] Fuller | Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist[END_REF].

Ontogenesis of adrenal glands in Amphibians

Like in mammals, the adrenal gland in amphibian is constituted of two tissues, different in function and in embryonic origin: the chromaffin tissue that produces the catecholamines and the steroidogenic tissue that produces glucocorticoid, mineralocorticoid, and androgenic hormones [START_REF] Norris | Vertebrate Endocrinology[END_REF]. In amphibians, the primary glucocorticoid is corticosterone.

While the adrenals in mammals have a characteristic cortical-medullary organization with distinct zonation, such distinctions are lacking in non-mammalian species. In Anurans, adrenocortical tissue corresponds to irregular nodules organized into a pair of inter-renal glands on the ventral surface of the kidneys. The glandular pattern is, on one hand, more medial and diffuse in frogs of the more primitive families and, on the other hand, more lateral and aggregated in the more advanced families [START_REF] Milano | Evolutionary trends in adrenal gland of anurans and urodeles[END_REF]. In Urodeles, the adrenal glandular structure is variable without a clear taxonomic pattern, although increased compactness of the gland and mingling of steroidogenic and chromaffin cells can be found. The compactness and aggregation of chromaffin and steroidogenic tissues therefore increase in the transition from primitive to advanced families, both in urodeles and anurans. Ontogenesis of the gland is similar in all amphibians studied. The chromaffin originates from neural crest cells by migration and the primordium of the steroidogenic tissue coincides with or is near to the mesonephric blastema. In Anuran, the gland develops on the kidney of mesonephric type by a moderate cell proliferation of the dorsal root of the dorsal mesentery leading to the interrenal tissue, homologous with the mammal's adrenal cortex. The persistence of the mesonephros will preserve the contact established between the two organs during ontogenesis. Until the end of metamorphosis (biological process by which larva physically transforms after birth into an adult, involving a conspicuous and relatively abrupt change in the animal's body structure, allowing evolution from aquatic to a terrestrial or semi-terrestrial lifestyle), morphogenesis of the adrenal gland is similar in all amphibians studied. After metamorphosis in the advanced anurans, the adrenal gland may reach its definitive position before sexual maturity by various means, among which active cellular movements prevail. The inter-renal gland is generally more active just before metamorphosis and metamorphic climax. The corticosteroids (CS) plasma levels are low-to-nondetectable before metamorphosis, but increase significantly at metamorphic climax, in parallel with the rise in thyroid hormones (TH), the metamorphosis trigger [START_REF] Jaudet | Variations in aldosterone and corticosterone plasma levels during metamorphosis in Xenopus laevis tadpoles[END_REF]. Surprisingly, whole-body CS content increases before metamorphosis and then declines to be low at metamorphic climax or in some cases shows a small increase at metamorphic climax [START_REF] Glennemeier | Small changes in whole-body corticosterone content affect larval Rana pipiens fitness components[END_REF][START_REF] Kloas | Stage-Dependent Changes in Adrenal Steroids and Catecholamines during Development inXenopus laevis[END_REF]. Whether these findings represent species differences or whether changes in wholebody CS content are not representative of changes in plasma concentrations is currently unknown. Aldosterone plasma levels first show a significant peak at the beginning of the climax and again at the middle of the climax. Whole-body aldosterone peak production is detected before metamorphosis and declines thereafter as observed for corticosteroids [START_REF] Glennemeier | Small changes in whole-body corticosterone content affect larval Rana pipiens fitness components[END_REF][START_REF] Kloas | Stage-Dependent Changes in Adrenal Steroids and Catecholamines during Development inXenopus laevis[END_REF].

The neuroendocrine system regulates the production of hormones by the adrenal and thyroid glands (Denver, 2009a). Hypothalamic corticotropin-releasing factor (CRF) is a common, central regulator of pituitary adrenocorticotropic hormone (ACTH) secretion and thyroidstimulating hormone (TSH) in tadpoles. By regulating TSH and ACTH secretion, and consequently the production of TH and CS, CRF controls the timing of metamorphosis integrating developmental progression and environmental signals. Thus, TH is considered as the primary morphogen of metamorphosis, while CS synergize with TH to promote metamorphic changes (Denver, 2009b). Aldosterone could play a part in the differentiation of adult skin and a role in the conquest of land [START_REF] Colombo | Aldosterone and the conquest of land[END_REF]. However, the history of CS seems more linked to the struggle for survival and environmental resources (Denver, 2009b).

Interestingly, mast cells, implicated in the regulation of aldosterone secretion, primarily appear in amphibian and their density follows a seasonal variation, with a rise in summer, linked to metamorphosis and amphibians' way out of water [START_REF] Lopez | Role of Mast Cells in the Control of Aldosterone Secretion[END_REF].

Ontogenesis of the adrenal gland and the mineralocorticoid pathway in Mammals 4.3.1 Zona Glomerulosa and CYP11B2 Expression

The adrenal cortex originates from the intermediate mesoderm while the medulla develops from the neuroectoderm and colonizes the adrenal cortex around 6-7 GW. In humans, the coelomic epithelium proliferates starting from 4 GW to form the urogenital crest, which will give rise to the adrenal glands as well as the gonads and the kidneys. Then, the adrenogonadal primordium individualizes from the renal outline, and splits into the gonadal and adrenal primordium. Around 8 GW in humans, two different histological layers appear within the adrenal primordium, composed of the external definitive zone (DZ), and the internal fetal zone (FZ), which represents 80% of the volume of the adrenal cortex at this stage. During the second trimester of gestation, a transition zone (TZ) individualizes between the definitive and fetal zones (Mesiano and Jaffe, 1997a). The fetal adrenal gland is dynamic with simultaneous proliferation of progenitor cells within the subcapsular layer, centripetal migration and cell apoptosis [START_REF] Drelon | Adrenal cortex tissue homeostasis and zonation: A WNT perspective[END_REF], the latter being mainly localized in the internal compartment [START_REF] Ishimoto | Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit[END_REF]. Many factors are involved in the human adrenal gland development i.e. hormonal factors, transcription factors and growth factors. ACTH is one of the main hormonal factor involved in this process, secreted as early as 8 GW by the fetal pituitary [START_REF] Ishimoto | Adrenocorticotropin preferentially up-regulates angiopoietin 2 in the human fetal adrenal gland: implications for coordinated adrenal organ growth and angiogenesis[END_REF]; however, it has been demonstrated that pituitary Luteinizing Hormone (LH) and placental human Chorionic Gonadotropin (hCG) also contribute to adrenal development [START_REF] Kero | Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex[END_REF]. SF1 (Steroidogenic Factor 1) and DAX1 (DSS-AHC critical region on the X chromosome, gene 1) are two essential transcription factors involved in adrenal cortex development, both being expressed from 33 days post-conception within the adrenogonadic primordium [START_REF] Suntharalingham | DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease[END_REF]. SF1 acts as a regulator of many genes involved in steroidogenesis including the ACTH receptor gene, StAR, CYP17, HSD3B1, CYP21, and CYP11B1. In addition, DAX1 and SF1 demonstrate complex functional interactions. Indeed, DAX1 is a transcription repressor of SF1 target genes, such as StAR, and is able to inhibit transcriptional activation mediated by SF1 [START_REF] Lalli | Targeting DAX-1 in embryonic stem cells and cancer[END_REF]. The adrenal gland development is also regulated by many growth factors such as bFGF (basic Fibroblast Growth Factor), EGF (Epidermal Growth Factor), IGF-I (Insulin-like Growth Factor I), IGF-II (Insulin-like Growth Factor II), and the TGFβ (Transforming Growth Factor β) family. For example, IGF-II is thought to stimulate the proliferation of steroidogenic cells and is involved in the activation of steroidogenesis mediated by ACTH (Mesiano and Jaffe, 1997b). The three areas of the fetal cortex (ZD, ZT and ZF) are morphologically and functionally different, depending on the selective expression of genes involved in steroidogenesis, thus allowing specificity for hormone biosynthesis [START_REF] Narasaka | Temporal and spatial distribution of corticosteroidogenic enzymes immunoreactivity in developing human adrenal[END_REF]. The definitive zone expresses both the 3HSD2 and CYP11B2 enzymes allowing for aldosterone biosynthesis. Recent studies showed that 3HSD2 is expressed starting from 18 GW in both definitive and fetal zones whereas expression of CYP11B2 only appears around 24 GW and is restricted to the subcapsular layer of the adrenal gland [START_REF] Coulter | Functional maturation of the primate fetal adrenal in vivo: 3. Specific zonal localization and developmental regulation of CYP21A2 (P450c21) and CYP11B1/CYP11B2 (P450c11/aldosterone synthase) lead to integrated concept of zonal and temporal steroid biosynthesis[END_REF][START_REF] Naccache | Temporal and spatial distribution of mast cells and steroidogenic enzymes in the human fetal adrenal[END_REF]. This relatively late expression may explain the absence of detection of plasma aldosterone in fetuses from 9 to 20 GW [START_REF] Johnston | The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester[END_REF]. Recent studies have also demonstrated a delayed CYP11B1 activity both in the ZD and ZT [START_REF] Kamrath | Reduced activity of 11β-hydroxylase accounts for elevated 17α-hydroxyprogesterone in preterms[END_REF][START_REF] Travers | Alterations of adrenal steroidomic profiles in preterm infants at birth[END_REF]. Aldosterone production begins during fetal life with detectable plasma concentrations in premature newborns as early as 25 GW [START_REF] Bourchier | Plasma aldosterone levels in the 1st week of life in infants of less than 30 weeks gestation[END_REF][START_REF] Martinerie | Aldosterone-Signaling Defect Exacerbates Sodium Wasting in Very Preterm Neonates: The Premaldo Study[END_REF]. Plasma aldosterone concentration increases until term [START_REF] Martinerie | Aldosterone-Signaling Defect Exacerbates Sodium Wasting in Very Preterm Neonates: The Premaldo Study[END_REF], in relation to a fetal neo-synthesis [START_REF] Bayard | Transplacental passage and fetal secretion of aldosterone[END_REF].

In mice, organogenesis of the adrenal gland follows the same developmental stages during gestation (which lasts approximately 21 days long). It begins on the 9 th day of gestation (E9). Zoning begins around E12, and the different areas of the cortex are identifiable at E16. Plasma aldosterone concentrations are detected in the fetus as early as E16 [START_REF] Wotus | Development of adrenal zonation in fetal rats defined by expression of aldosterone synthase and 11beta-hydroxylase[END_REF].

Thus, the establishment of aldosterone biosynthesis from the fetal stage appears as wellpreserved among mammals. At birth, the adrenal gland in a full-term newborn is capable of secreting large amounts of aldosterone, with circulating concentrations usually 10-fold higher than in an adult. Plasma aldosterone concentration will then decrease gradually during the first year of life in humans to reach concentrations close to that of the adult, around the age of 1 year [START_REF] Martinerie | Aldosterone-Signaling Defect Exacerbates Sodium Wasting in Very Preterm Neonates: The Premaldo Study[END_REF].

MR, 11HSD2 and Target Genes

MR expression during renal development shows a particular profile with a biphasic expression. It is followed in parallel by all the other players of the mineralocorticoid signaling pathway, expressed in the distal parts of the nephron (11HSD2 enzyme and target genes). This biphasic renal expression profile is extremely well-preserved between mice and humans (Figure 4). Renal expression of MR, 11HSD2, and MR target genes is transient during gestation and E16 and E18 in mice), then subsequently decreases as the term of birth approaches, before increasing again during the postnatal period, after the first week of life in mice. Renal expression of MR then increases very gradually during the first year of life in humans, along with the decrease in plasma aldosterone concentrations (Martinerie et al., 2009b). Thus, the mineralocorticoid signaling pathway is repressed in the kidney at birth, both in mice and humans. In contrast, this expression pattern is not identical in other organs where the mineralocorticoid signaling pathway is also expressed, such as the lung [START_REF] Martinerie | The mineralocorticoid signaling pathway throughout development: expression, regulation and pathophysiological implications[END_REF]. Indeed, while in the heart and brain, expression of the MR and of the mineralocorticoid signaling pathway undergoes the same variation during development, the decrease of expression is not observed in the lung at the time of birth, where it is, on the contrary, maintained (Figure 4). The expression of this signaling pathway is therefore tissuespecific and variable during development, particularly in the renal tubule, identically between mice and humans, suggesting an important physiological role in the preparation and/or the adaptation to extrauterine life.

Physiological Role During the Perinatal Period?

It seems relevant to question the role of this tissue-specific and temporal expression pattern of the mineralocorticoid pathway during development. The first element to consider concerns the fetal period. Interestingly, both in mice and in humans, the appearance of MR at E16 and around 15-20 GW, respectively, corresponds to the initiation phase of skin keratinization [START_REF] Underwood | Amniotic fluid: not just fetal urine anymore[END_REF]. It is, thus, highly possible that from this stage of development and onward the exchanges between fetal internal environment and the amniotic fluid are no longer passive, and that a mode of regulation at the renal level becomes necessary and pivotal. Subsequently, changes in renal MR expression could be related to variations of tonicity (and sodium content) of the surrounding environment [START_REF] Underwood | Amniotic fluid: not just fetal urine anymore[END_REF], somehow reminiscent of what is observed in fish. As mentioned in chapter 4.1, fishes, in particular salmons, express MR in their gills. When they acclimate from a freshwater environment to a saltwater environment during their life, MR expression adapts, being repressed, and inversely, upregulated when salmons return to freshwater, thus making it possible to maintain the water and sodium balance in the interior environment [START_REF] Kiilerich | Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro[END_REF]. Similarly, the osmolality of the amniotic fluid is stable in mice up to E16.5, where it decreases sharply (in parallel with the increase in MR renal expression), preceding a sharp increase before birth [START_REF] Cheung | Amniotic fluid volume and composition in mouse pregnancy[END_REF][START_REF] Desai | Reversal of pregnancy-mediated plasma hypotonicity in the near-term rat[END_REF] which coincides with the decrease in renal MR expression (Martinerie et al., 2009b). In addition, in humans, after birth, the newborn kidney must adapt from an aquatic environment to an air environment. The newborn must adjust to a very low sodium intake from breast milk, which further decreases during the first days of life [START_REF] Koo | Breast milk sodium[END_REF] (again reflecting the gradual increase in renal MR expression after the first week of life). At birth, the newborn kidney lacks MR expression, thus making it unresponsive to aldosterone. As we have seen above, aldosterone is secreted in large quantities by the adrenal gland in late pregnancy and at birth. This relative renal resistance to its action leads to a state of transient pseudo-hypoaldosteronism, associating hyponatremia (by sodium depletion), hyperkalemia, urinary sodium and water losses, accounting for neonatal weight loss observed physiologically during the first days of life (Martinerie et al., 2009a). Conversely, expression of MR is maintained in the lung at birth. The lung can therefore respond to high concentrations of aldosterone, and thus allow the resorption of pulmonary fluid, through expression of ENaC, the alpha subunit being a target gene of the aldosterone-MR complex [START_REF] Helve | Low expression of human epithelial sodium channel in airway epithelium of preterm infants with respiratory distress[END_REF].

Kidneys are then able to eliminate this excessive fluid. Finally, aldosterone could also have a direct role on the blood vessels and allow an increase in systemic vascular resistance at birth [START_REF] Romagni | Aldosterone induces contraction of the resistance arteries in man[END_REF]. Aldosterone therefore appears to be a central hormone in the adaptation to extrauterine life. Interestingly, regarding evolution, aldosterone is first detected in the lungfish, primary living being able to breathe, and in amphibians, whose ancestors came out of water during the terrestrialization, emphasizing this hypothesis (Figure 3).

Animal Models and Pathophysiological Situations Demonstrating this

Central Role in Neonatal Adaptation

Defects in the Activation of the Mineralocorticoid Signaling Pathway

The physiological importance of the mineralocorticoid signaling pathway is largely underscored by human pathologies as well as comforted by the phenotypes of recently generated knock-out animal models (both in mammals and in fish). The total as well as cellspecific gene inactivation have further deciphered the functional aspect and the molecular events involved in the mineralocorticoid signaling. Approximately one hundred MR loss-of function mutations presenting with a pseudohypoaldosteronism have been reported in humans (Zennaro and Fernandes-Rosa, 2017) as opposed to the unique MR gain-of-function mutation described in a family in which affected carriers presented with early arterial hypertension exacerbated during pregnancy [START_REF] Geller | Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I[END_REF]. The major role of MR in sodium and water homeostasis has been further corroborated by the phenotype of animal models. For instance, total MR knock-out mouse model has been generated almost three decades ago [START_REF] Berger | Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism[END_REF] and demonstrated that despite a normal in utero development, newborn mice prematurely die at 10 days of life from severe salt and water wasting that could be partially successfully treated with salt supplementation through intra-peritoneal injections [START_REF] Bleich | Rescue of the mineralocorticoid receptor knock-out mouse[END_REF]. In addition, a siRNA strategy against MR in the rat [START_REF] Lim | Silencing of the mineralocorticoid receptor by ribonucleic acid interference in transgenic rats disrupts endocrine homeostasis[END_REF] further demonstrated the importance of renal MR expression for an appropriate water and sodium homeostasis. Cellspecific and sometimes inducible MR gene invalidation including principal renal cells [START_REF] Ronzaud | Inducible renal principal cell-specific mineralocorticoid receptor gene inactivation in mice[END_REF]), cardiomyocytes (Ouvrard-Pascaud et al., 2005), endothelial cell [START_REF] Laursen | Endothelial mineralocorticoid receptor ablation does not alter blood pressure, kidney function or renal vessel contractility[END_REF], macrophage [START_REF] Rickard | Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/saltinduced cardiac fibrosis and increased blood pressure[END_REF], adipocyte [START_REF] Caprio | Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis[END_REF], neuronal [START_REF] Van Weert | Mechanistic Insights in NeuroD Potentiation of Mineralocorticoid Receptor Signaling[END_REF] have also elucidated key molecular events regulated by MR.

Constitutive corticosteroid knockout zebrafish and medaka which constitute viable animal models of corticosteroid receptor gene inactivation have been generated [START_REF] Sakamoto | A possible principal function of corticosteroid signaling that is conserved in vertebrate evolution: Lessons from receptor-knockout small fish[END_REF] and besides the role of MR in osmoregulation notably in mammals, these models allowed to point out towards a well conserved function of corticosteroid receptor in vertebrates integrating brain-behavior and visual responses, consistent with the presence of MR in the mammal retina [START_REF] Zhao | Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy[END_REF]. These studies in fish underscore that MR signaling is clearly not restricted to osmoregulation but may have a wider physiological impact that remains to be further elucidated [START_REF] Rossier | Osmoregulation during Long-Term Fasting in Lungfish and Elephant Seal: Old and New Lessons for the Nephrologist[END_REF]. Concerning ligand inactivation in humans, approximately forty-five inactivating mutations of the CYP11B2 gene, encoding the cytochrome P450 enzyme aldosterone synthase responsible for aldosterone synthesis and production have been described to date [START_REF] Miao | Analysis of heterozygous mutations in the CYP11B2 gene causing congenital aldosterone synthase deficiency and literature review[END_REF]. Aldosterone deficiency syndrome is a rare autosomal recessive disorder in infants characterized by hyponatremia, severe hyperkalemia, associated with salt wasting, dehydration and failure to thrive contrasting with low plasma aldosterone concentrations while 18-hydroxycorticosterone concentration might differentiate the level of enzymatic defect. The recent liquid chromatography coupled to mass spectrometry (LC-MS/MS) method should now facilitate quantification and identification of appropriate steroid levels both in human plasma and urinary samples [START_REF] Pussard | Urinary steroidomic profiles by LC-MS/MS to monitor classic 21-Hydroxylase deficiency[END_REF][START_REF] Travers | Multiplexed steroid profiling of gluco-and mineralocorticoids pathways using a liquid chromatography tandem mass spectrometry method[END_REF]. Genetic analyses, notably by next generation sequencing, demonstrated classical genetic alterations, the most common being missense and nonsense mutations, leading to an impaired enzymatic activity [START_REF] Miao | Analysis of heterozygous mutations in the CYP11B2 gene causing congenital aldosterone synthase deficiency and literature review[END_REF].

Transient Pseudohypoaldosteronism

In addition to these genetic diseases, there are pathological situations where a transient, nonphysiological pseudohypoaldosteronism appears [START_REF] Bogdanović | Transient type 1 pseudo-hypoaldosteronism: report on an eight-patient series and literature review[END_REF]. These pseudohypoaldosteronisms result in hyponatremia, hyperkalemia, metabolic acidosis and severe dehydration with major urinary sodium loss. They are essentially linked to the occurrence of an infection of the upper urinary tract (pyelonephritis) with or without underlying uropathy; and have the particularity of occurring mainly in infants under 3 months of age, most notably in males [START_REF] Bogdanović | Transient type 1 pseudo-hypoaldosteronism: report on an eight-patient series and literature review[END_REF]. They will disappear with the correction of the urinary tract infection, but during the acute phase, they will require active management by sodium and water supplementation. The pathophysiology may be related to low renal expression of the mineralocorticoid pathway during this period of life, and to inflammation (through the activation of NF-B factor) that may further downregulate MR expression and activation [START_REF] De Seigneux | NF-kappaB inhibits sodium transport via down-regulation of SGK1 in renal collecting duct principal cells[END_REF]. The fact that boys seem more particularly affected, could be explained by a sexual dimorphism in the renal expression of the mineralocorticoid signaling pathway [START_REF] Dumeige | Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences[END_REF], making boys more sensitive to a decline in its expression.

Specificity of the Premature Infants

The mineralocorticoid signaling pathway seems essential in the postnatal period. Thus, it can be wondered if the premature infant, whose organ maturation is not yet completed, has the capacity to adapt at birth. Aldosterone secretion increases gradually during fetal life, starting from 25 GW [START_REF] Bourchier | Plasma aldosterone levels in the 1st week of life in infants of less than 30 weeks gestation[END_REF][START_REF] Martinerie | Aldosterone-Signaling Defect Exacerbates Sodium Wasting in Very Preterm Neonates: The Premaldo Study[END_REF]. Very premature infants (birth before 32 GW), therefore have a limited capacity for aldosterone neo-synthesis (linked to an overall immaturity of the adrenal gland associated with a specific lack of biological activity of the 11--hydroxylase enzyme [START_REF] Kamrath | Reduced activity of 11β-hydroxylase accounts for elevated 17α-hydroxyprogesterone in preterms[END_REF][START_REF] Travers | Alterations of adrenal steroidomic profiles in preterm infants at birth[END_REF]. The adrenal gland is not able to adapt to neonatal changes, and aldosterone concentrations remain 3 to 4 times lower than in a full-term newborn (around 300 pg/mL compared to 1000 pg/mL on average, by RIA measurement) [START_REF] Martinerie | Aldosterone-Signaling Defect Exacerbates Sodium Wasting in Very Preterm Neonates: The Premaldo Study[END_REF]. It should be noted, however, that these concentrations are 4 times higher than that of an adult (on average 80 pg/mL) again underlining the importance of this hormone, which must be secreted in large quantities, for optimal postnatal adaptation. Thus, despite a transient MR expression at the renal level in very premature infants between approximately 25 and 30 GW, allowing the kidney to respond transiently to the action of aldosterone [START_REF] Martinerie | Aldosterone-Signaling Defect Exacerbates Sodium Wasting in Very Preterm Neonates: The Premaldo Study[END_REF](Martinerie et al., , 2009b)), the relatively low secretion of aldosterone does not permit an active sodium reabsorption during the first weeks of life. Likewise, the lung has difficulty reabsorbing alveolar fluid [START_REF] Helve | Low expression of human epithelial sodium channel in airway epithelium of preterm infants with respiratory distress[END_REF].

Conclusions

The mineralocorticoid signaling pathway therefore appears to be a primary pathway for adaptation to extrauterine life. Regarding evolution, while MR is already expressed in fish, involved in the regulation of sodium homeostasis between freshwater and saltwater, fine regulation of the mineralocorticoid pathway appears with its main hormone, aldosterone, in one of the first living being that evolves outside water, the amphibian. Similarly, aldosterone secretion increases throughout gestation in mammals, preparing the fetus for its extrauterine life, reaching levels in full-term newborns approximately 10-fold higher than that of the adults.

Defects in aldosterone production or activation of the mineralocorticoid pathway result in neonatal maladaptation at birth. In premature newborns, due to the relative low levels of circulating aldosterone, a sodium wasting syndrome sets in, causing dehydration, hyponatremia and hyperkalemia, which can be life-threatening. Altogether, results obtained from comparative evolution and over the last ten years specifically in mammals, have shed light on a central role for mineralocorticoid signaling and have pointed out to new therapeutic opportunities for preventing urinary sodium loss in very premature infants. Binding of AngII to AT1R leads the depolarization of the cell membrane that inhibits potassium channels and the Na + ,K + -ATPase and subsequently triggers an influx of extracellular Ca 2+ and a release of Ca 2+ from the endoplasmic reticulum, that activates calcium/calmodulin-dependent protein kinases (CaMKs). Then, CaMKs increase expression and phosphorylation of transcription factors such as Nurr1 and CREB1 thus stimulating expression of the CYP11B2 gene, which encodes the aldosterone synthase, the enzyme that catalyzes the last steps of aldosterone biosynthesis. AngII: Angiotensin II; AT1R: Angiotensin 1 Receptor; TASK 1/3: potassium channels.

Figures Legends:

  rhythmicity of renal sodium reabsorption since PER1 belongs to the circadian clock gene family. Beyond this classical model of aldosterone action, recent data obtained from ChIP experiments revealed that MR can also indirectly bind to recognition motifs for other transcription factors (FOX, EGR1, AP1, PAX5), suggesting functional interactions of MR with other transcription factors through tethering mechanisms, thus enabling the modulation of target gene expression (Le Billan et al., 2015).

Figure 1 :

 1 Figure 1: Physiological regulation of aldosterone production in steroidogenic cells of the

Figure 2 :

 2 Figure 2: Model of mineralocorticoid signaling in the distal polarized tubular cell of the

Figure 3 :

 3 Figure 3: Expression of corticosteroid receptors and their ligands throughout evolution.

Figure 4 :

 4 Figure 4: Mineralocorticoid receptor expression profile during development in mice and

This research was supported by grants from the French National Institute for Health and Medical Research (Inserm), the University Paris-Saclay, and the French National Agency for Research (ANR), grant no. ANR-20-CE14-0015 (PERIMIRE).