# Tissue-Specific Expression and Regulation of the Mineralocorticoid Receptor During Development

Laetitia Martinerie, Imène Hani, Julie Perrot, Say Viengchareun

► To cite this version:

Laetitia Martinerie, Imène Hani, Julie Perrot, Say Viengchareun. Tissue-Specific Expression and Regulation of the Mineralocorticoid Receptor During Development. Journal of Endocrinology, 2026, 268 (1), pp.e250265. 10.1530/JOE-25-0265. hal-05465169

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# Tissue-Specific Expression and Regulation of the Mineralocorticoid Receptor During Development

Laetitia Martinerie<fnref n="1" />,<fnref n="2" />,<fnref n="3" />, Imène Hani<fnref n="1" />, Julie Perrot<fnref n="1" />, Say Viengchareun<fnref n="1" />

Correspondence should be addressed to:

Say Viengchareun, PhD

Inserm U1185, Faculté de Médecine Paris-Saclay

Bâtiment Recherche, 63 rue Gabriel Péri,

94276, Le Kremlin-Bicêtre, France

E-mail : say.viengchareun@universite-paris-saclay.fr

<footnote n="1">¹ Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, 94276 Le Kremlin-Bicêtre, France ;</footnote>

<footnote n="2">² Endocrinologie Pédiatrique, Centre de Référence Maladies Endocriniennes Rares de la Croissance et du Développement, Hôpital Universitaire Robert-Debré GHU APHP Nord, 75019 Paris, France ;</footnote>

<footnote n="3">³ Université Paris Cité, Faculté de Santé, UFR de Médecine, Paris, France.</footnote>
Abstract

This review summarizes current knowledge on the mineralocorticoid receptor (MR), a nuclear
receptor encoded by the *NR3C2* gene, and its ligand aldosterone. In epithelial tissues like the
kidney, colon, salivary glands and skin, particularly within the sweat glands, the MR plays a key
role in regulating sodium reabsorption. In non-epithelial tissues such as the brain, adipose tissue,
and heart, glucocorticoids are the main physiological MR ligands due to the absence of the 11β-
hydroxysteroid dehydrogenase type 2. MR expression begins during development with tissue-
specific patterns. In the kidney, MR levels peak mid-gestation, decrease at birth then increase
postnatally. Loss of MR function, as observed in pseudohypoaldosteronism type 1 causes salt-
wasting syndrome. Similar patterns are seen in the heart and brain, especially the hippocampus,
where it influences stress regulation. On the contrary, MR expression is maintained at birth in the
lung for neonatal fluid clearance *via* epithelial sodium channels. It is also present in tissues like
skin, retina, and gastrointestinal tract, indicating broad physiological roles. MR expression during
fetal development correlates with adaptations to extra-uterine life, like changes in amniotic fluid
osmolality and aldosterone levels. MR gene expression and activity are tightly regulated through
multiple mechanisms. These include transcriptional control *via* two promoters, post-
transcriptional regulation involving RNA-binding proteins and microRNAs, and post-translational
modifications such as phosphorylation, sumoylation, and ubiquitination. These regulatory levels
ensure appropriate MR function across different tissues and developmental stages and may have
implications for conditions such as hypertension and heart failure.
70 **Keywords**

71

72 Aldosterone, Mineralocorticoid receptor, sodium homeostasis, neonatal period, development

73 **Abbreviations**

74

75 D: Postnatal Day; MR : Mineralocorticoid Receptor; NR3C2 : Nuclear Receptor Subfamily 3 Group

76 C Member 2; 11β-HSD2 : 11β-Hydroxysteroid Dehydrogenase Type 2; GR : Glucocorticoid

77 Receptor; ENaC : Epithelial Sodium Channel; SCNN1A : Sodium Channel Epithelial 1 Alpha Subunit;

78 Na+/K+-ATPase : Sodium-Potassium Adenosine Triphosphatase; SGK1 : Serum and Glucocorticoid-

79 Induced Kinase 1; GILZ : Glucocorticoid-Induced Leucine Zipper; WNK1 : With No Lysine [K] Kinase

80 1; NCC : Sodium-Chloride Cotransporter; NKCC1/2 : Sodium-Potassium-Chloride Cotransporter 1

81 and 2; ROMK : Renal Outer Medullary Potassium Channel; NGAL : Neutrophil Gelatinase-

82 Associated Lipocalin; PER1 : Period Circadian Regulator 1; PHA1 : Pseudohypoaldosteronism Type

83 1; UTI : Urinary Tract Infection; E : Embryonic Day; D ; GW : Gestational Week; AF-2 : Activation

84 Function-2; Hsp : Heat Shock Protein; FKBP52 : FK506 Binding Protein 52; SRC-1, SRC-2 : Steroid

85 Receptor Coactivators 1 and 2; PGC-1α : Peroxisome Proliferator-Activated Receptor Gamma

86 Coactivator 1-alpha; ELL : Eleven-Nineteen Lysine-Rich Leukemia Gene; DAXX : Death-Domain

87 Associated Protein; SMRT/NCoR : Silencing Mediator of Retinoic Acid and Thyroid Receptor /

88 Nuclear Receptor Co-Repressor; PIAS1 : Protein Inhibitor of Activated STAT 1; RT-PCR : Reverse

89 Transcription Polymerase Chain Reaction; RBP : RNA-Binding Protein; miRNA : MicroRNA; TonEBP

90 : Tonicity-Responsive Enhancer Binding Protein; Zfp36l1 : Zinc Finger Protein 36 Like 1; HuR :

91 Human Antigen R; HATs : Histone Acetyltransferases; HDACs : Histone Deacetylases; HDAC4 :

92 Histone Deacetylase 4; E1, E2, E3 : Enzymes involved in Ubiquitination/Sumoylation; WNK4: With

93 no lysine (K) protein kinase 4.

94
95

**Introduction**

96

Aldosterone, a steroid hormone synthesized in the *zona glomerulosa* of the adrenal cortex, is the main mineralocorticoid hormone (1). It functions by binding to the Mineralocorticoid Receptor (MR), a transcription factor, encoded by the *NR3C2* gene, which belongs to the nuclear receptor family (2,3). Several variants at both the RNA (4,5) and protein levels (6) have been identified. In the kidney, colon, salivary glands, and skin, particularly in the sweat glands, the MR is essential for epithelial electrolyte homeostasis, primarily by stimulating sodium reabsorption and facilitating potassium secretion. Glucocorticoid hormones such as cortisol in humans and corticosterone in rodents can also bind to MR. However, in epithelial tissues, this interaction is prevented by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts glucocorticoid hormones into inactive compounds (7,8). In contrast, glucocorticoid hormones serve as the main activators of MR in non-epithelial tissues like the brain, heart, and adipose tissues, where 11β-HSD2 is absent. The MR exhibits transient expression during critical developmental stages in both mouse and human models, especially within renal tissues. Indeed, its expression diminishes after birth but reappears during early postnatal development, suggesting a conserved role for MR signaling in developmental processes (9). The regulation of MR expression and activity is complex, involving multiple levels such as transcriptional, post-transcriptional, and post-translational mechanisms. This review emphasizes tissue-specific expression and regulation of MR throughout development.

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115 **MR-expressing tissues**

116 MR expression in the adult kidney was initially observed in the distal convoluted tubules, the loop
117 of Henle and the collecting tubules (10,11). Further research extended these findings, revealing
118 MR presence in the glomerulus, mesangial cells (12,13) and podocytes (14). Beyond the kidney,
119 MR is expressed in various epithelial tissues. In the gastrointestinal tract, significant sites include
120 the esophageal epithelium and segments of the small intestine (duodenum, jejunum, ileum) as
121 well as the colon (15,16). In the skin, MR is found in keratinocytes of the epidermis, hair follicles,
122 and sebaceous and sweat glands (17). MR presence is also observed in various other tissues,
123 including the lung (18,19), inner ear (20,21), eye such as the retina, iris, ciliary bodies (22-24), liver
124 (25) and the salivary glands (17,26). MR expression extends beyond epithelial tissues and has been
125 identified in a variety of non-epithelial cell types and organs. Notably, MR is expressed in several
126 immune cell populations, including mononuclear leukocytes (27), T lymphocytes (28),
127 macrophages (29), and neutrophils (30). In the cardiovascular system, MR is present in
128 cardiomyocytes and endothelial cells (31), as well as in vascular smooth muscle cells of large
129 vessels such as the aorta (32). Additionally, MR expression has been demonstrated both in brown
130 and white adipose tissue (33-36), and in various regions of the brain, including the hypothalamus
131 (37,38) and hippocampus (39,40). Further evidence indicates its expression in reproductive organs,
132 such as Leydig cells of the testes (41), ovaries and the uterus (42), suggesting a role in reproductive
133 functions. Finally, MR expression has been identified in the placenta (43). Given its widespread
134 presence across numerous tissue types, MR is now regarded as a widely expressed receptor
135 involved in regulating numerous physiological processes. Dysregulation of its expression or
136 activation contributes to the development of diseases such as cardiovascular and renal disorders.

137
138 Genomic action of the MR in renal adult cells

139 In the absence of a ligand, the MR remains in cytoplasm, stabilized by a chaperone complex
140 consisting of Hsp70, Hsp90, p23, and FKBP52 (Fig. 1). This complex maintains the receptor in a
141 state ready to bind a ligand (3). Upon aldosterone binding, the MR dissociates from the complex,
142 undergoes conformational changes, such as Ligand-Binding Domain (LBD) compaction and H12
143 helix folding, and translocates to the nucleus, where it activates target gene expression (44).

144 Within the nucleus, MR forms either homodimers or heterodimers with the glucocorticoid
145 receptor (GR). These complexes bind mineralocorticoid response elements (MREs) to regulate
146 gene expression (45). Because MR and GR have highly conserved DNA-binding domains, they
147 recognize largely overlapping glucocorticoid/mineralocorticoid response element motifs.

148 Accordingly, many genomic regions in renal cells, particularly those harboring canonical
149 palindromic GRE/MRE sequences, are accessible to both receptors. MR recruits coactivators such
150 as SRC-1 and SRC-2, PGC-1α, and ELL via the Activation Function-2 (AF-2) domain and the N-
151 terminal region. This recruitment process enhances transcription by increasing chromatin
152 accessibility, thereby facilitating gene activation (46-48). Corepressors such as Gemin4, NF-YC,
153 DAXX, SMRT/NCoR, PIAS1 bind the LBD and inhibit transcription through histone deacetylases,
154 with activity depending context (49-53). The main target genes of MR are involved in sodium
155 reabsorption, including SCNN1A (ENaC α-subunit), ATP1A1 (Na+/K+-ATPase α1-subunit), SGK1,
156 GILZ, and WNK1 (54,55). ENaC functions in the kidney, colon, and lung, while SGK1 enhances ENaC
157 stability (56,57). Aldosterone-induced WNK1 kinase also activates SGK1 and regulates NCC,
158 NKCC1/2, and ROMK (58). GILZ promotes ENaC expression and suppresses ERK signaling (59).
159 Additional MR targets include NGAL, which is involved in NCC regulation and associated with
160 hypertension (60), and PER1, which plays a role in circadian control of many organs including renal
161 function (61).
162

## MR expression during development

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MR expression is tightly controlled in a tissue-specific manner throughout development, which may have significant implications for pathophysiology during the neonatal period (Table 1). MR expression is detectable as early as embryonic day 13.5 (E13.5) in mice across various tissues, including the pituitary gland, heart, muscles, and meninges. Subsequently, this expression extends to the gut, kidney, thymus, specific lung regions, and several brain areas such as the hippocampus, rhinencephalon, and hypothalamus (62). In humans, MR transcripts are detectable in multiple fetal tissues as early as six gestational weeks (GW) (63). The expression of MR, in relation to GR and $11\beta$HSD2, will be described in the principal mineralocorticoid target tissues, and its functional role will be discussed in the context of the transition from fetal to neonatal life.

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## Kidney

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In the kidney, MR transcript and protein levels have been extensively studied at various developmental stages in both murine and human renal samples using techniques such as quantitative RT-PCR, immunohistochemistry, and immunoblotting. Findings indicate that MR is temporarily expressed in the distal convoluted tubule and cortical collecting duct cells of mice between E16 and E20, and in humans between 15 and 25-30 GW (18,64). Notably, at birth, renal MR expression markedly declines, with both MR mRNA and protein levels falling below detectable levels. After birth, MR expression exhibits a biphasic pattern, increasing again until D8 in mouse kidney and throughout early childhood in humans, before reaching adult levels (64). This expression profile parallels that of $\alpha$ENaC and $11\beta$HSD2, and differs from other genes expressed in the same cells, such as aquaporin 2 or the GR. These observations underscore a time-specific expression pattern unique to the mineralocorticoid signaling pathway in the kidney, consistent across species, and suggest a pivotal role in physiological processes (64). Indeed, the loss of function or reduced activity of MR signaling is mainly associated with sodium wasting and
186 difficulties in adaptation during the postnatal period. Mice lacking MR in all target tissues exhibited
187 normal prenatal development. However, after birth, they displayed symptoms of
188 pseudohypoaldosteronism, such as hyperkalemia, hyponatremia, and increased levels of
189 aldosterone, renin, and angiotensin II. These mice typically died around D10 due to renal sodium
190 loss. Administration of exogenous NaCl prevented sodium loss and allowed survival into
191 adulthood, although renal salt loss continued despite treatment (65,66). Autosomal dominant
192 pseudohypoaldosteronism type 1 (PHA1), also known as renal PHA1, is a rare genetic disorder in
193 humans resulting from mutations in the *NR3C2* gene. These mutations compromise the function
194 of the MR, leading to decreased receptor expression (haploinsufficiency). The condition can be
195 inherited or occur spontaneously as *de novo* mutations. More than 50 variants have been
196 identified across all exons of the *NR3C2* gene, with impact on the DNA-binding and ligand-binding
197 domains. These variants can impair MR function by disrupting hormone binding, gene activation,
198 and receptor localization. Some mutations even exert dominant negative effects, potentially
199 interfering with normal receptor activity (67). Although most cases result from dominant
200 mutations, a rare recessive form has been documented, involving two distinct *NR3C2* gene
201 mutations, specifically p.[Ser166Stop] and p.[Trp806 Stop], which lead to minimal residual MR
202 activity that remains compatible with life (68). The condition is estimated to affect 1 in 80,000
203 newborns, although this may be underestimated. It typically presents in newborns as a salt-
204 wasting syndrome, with symptoms like low sodium, high potassium, metabolic acidosis, and
205 dehydration. These symptoms can occur despite elevated levels of aldosterone and renin. Some
206 infants may require sodium supplementation, but many improve after infancy and remain healthy
207 into adulthood, although their renin and aldosterone levels often remain elevated (69). In addition
208 to genetic causes, transient pseudohypoaldosteronism can result from urinary tract infections
209 (UTIs), particularly in male infants under three months of age (70). These cases are like PHA1 but
210 typically resolve with infection treatment and supportive care. The condition may involve
211 temporary repression of the mineralocorticoid signaling pathway, already low at this
212 developmental age (64), potentially exacerbated by inflammation (71), sexual dimorphism and
213 developmental immaturity (72). Premature infants are also at increased risk of salt-wasting due to
214 adrenal gland immaturity and a deficiency in the biological activity of the 11β-hydroxylase enzyme
215 (73), an enzyme required for aldosterone and cortisol biosynthesis in the adrenal cortex (74),
216 leading to inadequate aldosterone production (75). Although MR expression occurs in the kidney
217 early in gestation (64), the deficiency of aldosterone impairs effective sodium retention (75).
218 Currently, a clinical trial is investigating whether early supplementation with mineralocorticoids
219 can reduce sodium loss in affected infants (clinicaltrials.gov ID NCT03001089).

220 Brain

221 The ontogeny of MR in the brain, particularly within the hippocampus, is well-documented. MR
222 and GR are co-expressed in this region, facilitating coordinated regulation of stress responses,
223 neuronal activity, and behavior. In rodent models, MR expression begins around E14-E15
224 (62,76,77), then decreases until postnatal day 10 (D10), before increasing slightly and stabilizing
225 by D20 (77). Levels of MR protein are low at birth but gradually increase after birth (9,78). Research
226 indicates a steady, moderate rise in GR transcript and protein levels after birth (78-80). In the
227 human hippocampus, both MR and GR are detectable by 24 GW and remain stable until 34 GW
228 (77). However, it remains uncertain whether MR expression beyond week 34 follows a similar
229 developmental pattern as observed in mice. In guinea pigs, hippocampal MR decreases while GR
230 levels increase during development (81). The pituitary gland exhibits an earlier expression of GR
231 at embryonic E8 compared to MR at E12. GR is present in over 95% of cells, whereas MR is found
232 in approximately 40% (82). During embryonic development, MR expression diminishes but
233 increases postnatally across various species, including chicks, rats, mice, and primates, eventually
234 stabilizing in adulthood (79,83-86). Overall, MR expression in the hippocampus and pituitary
235 follows a specific developmental pattern around birth, like its behavior in the kidney, and is
236 conserved across species. Interestingly, high levels of 11βHSD2 are expressed in various regions of
237 the fetal brains of rats, mice, and humans (62,87,88), whereas in adult humans and rodents,
238 11βHSD2 expression and activity are restricted to the aldosterone-sensitive neurons (89-91) in the
239 nucleus of the solitary tract (NTS). This presence likely serves to prevent overstimulation of MR by
240 glucocorticoids during critical developmental periods, facilitating aldosterone-specific MR
241 signaling that may be essential for fetal and neonatal brain development.

242

243 **Heart**

244 The MR is expressed across multiple cardiac cell types, including cardiomyocytes, fibroblasts,
245 endothelial cells, and vascular smooth muscle cells, reflecting its diverse roles in both cardiac
246 development and pathological remodeling. However, the development of MR ontogeny in these
247 multiple cardiac cell types has been insufficiently studied. *In situ* hybridization analyses in mice
248 have demonstrated that MR transcript levels in the heart begin at E13.5, decrease significantly by
249 E18.5, and then gradually increase after birth, mirroring expression patterns observed in the
250 kidney, pituitary, and hippocampus (62). More recent studies on MR expression in the hearts of
251 sheep fetuses have revealed a marked reduction from day 80 of gestation to the postnatal period
252 in the left ventricle, whereas expression in the right ventricle remains constant (92).

253

254 **Lung**

255 The lung is a key target for mineralocorticoid action, particularly at birth. In mice, MR expression
256 begins at E16 in type 2 pneumocytes and is sustained postnatally. Unlike other tissues, pulmonary
257 MR expression remains stable at birth (9,93,94). MR contributes to the regulation of lung fluid
258 composition (95) and is present in human fetal lung epithelial cells during early gestation,
259 alongside 11βHSD2. This is significant because the reabsorption of pulmonary fluid, which is vital
260 for newborns adapting to life outside the womb, is mainly controlled by ENaC (96,97). Additionally,
261 preterm infants with lower aldosterone production exhibit decreased pulmonary expression of the
262 three ENaC subunits, leading to difficulties in alveolar fluid reabsorption and respiratory distress
263 (98). These findings suggest that MR plays a vital role in pulmonary fluid reabsorption, which is
264 essential for the transition to an air-breathing environment in newborns.

265 **Skin**

266 MR expression has been identified in epidermal keratinocytes as well as in hair follicles, sebaceous
267 glands, and sweat glands in both human and mouse skin (17). Targeted overexpression of MR in
268 epidermal and follicular keratinocytes revealed two distinct phenotypes. Prenatal overexpression
269 led to early postnatal lethality, characterized by an eye-open phenotype, reduced hair follicle
270 development, and epidermal thinning with increased keratinocyte apoptosis at E18.5. Postnatal
271 overexpression, however, resulted in delayed alopecia and dermal cyst formation, preceded by
272 follicular dystrophy, while sparing the interfollicular epidermis (99). Analysis of MR expression
273 during development showed a peak at embryonic day 16.5, followed by a marked decline after
274 birth, indicating a transient role in skin development. In line with this, MR knockout mice exhibited
275 mild abnormalities at E17.5, including epidermal thickening and altered expression of
276 differentiation markers, which normalized postnatally, suggesting compensatory activity by the GR
277 (100,101).

278

279 **Other tissues**

280 MR is expressed in a variety of tissues beyond the kidney, heart, and brain, with distinct temporal
281 patterns during development. In this section, we summarize current knowledge of MR expression
282 and function in the placenta, retina, reproductive organs (testis and epididymis), gastrointestinal
tract, and developing skeletal system, highlighting both species-specific differences and developmental dynamics. However, research on MR expression and function across these tissues during development remains limited, underscoring the necessity for further studies. MR expression is detected as early as 6th gestational week (GW) in the human placenta, alongside the 11βHSD2 and the GR (63). MR transcripts are detectable in the inner retina of rats from D1 to D11 (102). An animal model for the retinopathy of prematurity shows a decrease in the neovascularization, a hallmark feature of the condition, when treated with AT1R inhibitors, that reduce aldosterone production (103). This suggests that the mineralocorticoid signaling pathway may play a role in the development of this pathology (104). Additionally, MR is immunodetected in rat epididymal epithelium from postnatal D1, with increasing expression levels until D28 (105), but is absent from the human fetal testis, at variance with GR and 11βHSD2 (63). In the developing gastrointestinal tract, MR transcripts are expressed throughout the small and large intestines but are absent in the stomach. The highest levels are found in the distal colon, with notable levels in the duodenum, exceeding those in the kidney (106). MR and 11βHSD2 co-localize in the embryonic mouse colon from E18.5, as demonstrated by in situ mRNA hybridization. In humans, MR is detectable in developing long bones and chondrocytes of the fetal rib from 6 GW, along with a low expression of GR and absent expression of 11βHSD2, with increasing levels observed after 12 weeks (63). Expression of MR and GR were detected in chondrocytes of the neonatal human rib (107). The tissue-specific and temporal expression pattern of MR during development raises questions regarding its functional role. During the fetal period, onset of renal MR expression at E16 in mice and around 15-20 GW in humans aligns with the onset of skin keratinization (108). This indicates a transition from passive to regulated exchanges between the fetal internal environment and amniotic fluid, which requires renal regulation. Later, modifications in renal MR expression may be associated with changes in the tonicity and sodium content of the surrounding
307 environment, similar to adaptive MR expression observed in fish gills during transitions between
308 freshwater and saltwater habitats (109). The osmolality of amniotic fluid in mice remains stable
309 up to E16.5, after which it decreases sharply, coinciding with increased renal MR expression
310 between E16.5 and E20 and subsequent physiological changes prior to birth (64,110,111). Finally,
311 MR exhibits a tissue-specific and temporal expression pattern crucial during the perinatal period
312 for adapting to extra-uterine life. Plasma aldosterone levels are significantly elevated at birth,
313 approximately ten times higher than in adults, and decrease postnatally, mirroring progressive
314 increased MR tissue expression from birth onwards (64,75). This suggests that the aldosterone-
315 MR signaling pathway is essential for adapting to life outside the amniotic environment. Elevated
316 aldosterone levels and sustained pulmonary MR expression at birth facilitate fluid resorption
317 through αENaC activation (96,97). Tissue-specific downregulation of MR expression may serve to
318 prevent excessive mineralocorticoid activation, especially in the kidney, aiding in the removal of
319 reabsorbed pulmonary fluids and contributing to physiological weight loss in neonates.
320 Evolutionary evidence supports the developmental importance of MR, which is already present in
321 fish and regulated by osmolality (109). Aldosterone first emerges in lungfish and amphibians,
322 underscoring its role in air-breathing animals (112).
323

324 Multilayered regulation of MR expression

325 The transcriptional regulation of the MR involves two promoters, P1 and P2, located upstream of
326 exons 1α and 1β, respectively. These promoters are conserved across species such as rats and
327 mice. The P1 proximal promoter exhibits higher basal activity, while P2 is specifically responsive to
328 aldosterone in a dose-dependent and MR-dependent manner. Transcription factors SP-1 and AP-
329 2, which bind within these regions, contribute to the regulation of MR gene expression, indicating
330 a complex control mechanism (113).
331 MR expression is also modulated post-transcriptionally by regulators that influence RNA stability
332 and translation, which are essential for gene expression and cellular adaptation. Key regulators
333 include RNA-binding proteins (RBPs) and microRNAs (miRNAs). RBPs bind specific transcripts to
334 modulate their stability: stabilizing RBPs extend transcript half-life (114), while destabilizing RBPs
335 promote degradation (115). In KC3AC1 principal cells, hypertonicity decreases MR transcript
336 levels, coinciding with increased expression of TonEBP, which activates Zfp36l1 encoding the
337 Tis11b RBP, leading to MR mRNA destabilization (116). Conversely, hypotonic conditions enhance
338 MR expression through HuR recruitment, which stabilizes MR transcripts and influences gene
339 transcription (117). HuR also affects MR transcript splicing, resulting in a dominant-negative Δ6
340 variant, thereby modulating receptor activity (5). MicroRNAs are small RNA molecules, typically
341 20-25 nucleotides in length, that regulate gene expression by affecting transcript stability or
342 translation. While they generally suppress gene expression, certain contexts allow them to
343 enhance translation (118). They target MR mRNA, with miR-135a and miR-124 inhibiting its
344 translation (119). Other miRNAs such as miR-181a, miR-454, miR-766, miR-466, miR-324-5p, and
345 miR-30c-2-3p modulate MR expression in various physiological and pathological conditions,
346 including hypertension, myocardial infarction, and cancer (120–124). Tonicity influences MR
347 signaling through miRNA interactions, involving HuR and other mechanisms.

348 Post-translational modifications of MR include phosphorylation, ubiquitination, sumoylation, and
349 acetylation, which collectively influence its function. Phosphorylation involves the addition of
350 phosphate groups to tyrosine, serine, or threonine residues. Several MR phosphorylation sites
351 have been identified, including Ser<sup>128</sup>, Ser<sup>250</sup>, Thr<sup>159</sup> in the N-terminal domain, Ser<sup>601</sup> in the NLS0
352 ligand-independent signal, and Ser<sup>843</sup> in the LBD (125–127). Phosphorylation at Ser<sup>843</sup> prevents
353 ligand binding and is restricted to distal nephron intercalated cells. Volume depletion decreases
354 Ser<sup>843</sup> phosphorylation via angiotensin II and WNK4, whereas hyperkalemia increases it.
355 Dephosphorylation enables aldosterone to activate apical proton pumps and Cl-/HCO3-
356 exchangers, promoting Cl- reabsorption, plasma volume expansion, and reduced K+ secretion
357 (128). Overall, MR phosphorylation modulates ligand affinity, cofactor interaction, DNA binding,
358 nuclear translocation, and non-genomic signaling, fine-tuning its activity.

359 Ubiquitination involves attaching ubiquitin molecules to lysine residues, targeting MR for
360 degradation *via* the proteasome, a process facilitated by enzymes E1, E2, and E3 (129).

361 Sumoylation involves attaching SUMO proteins to lysine residues, thereby modulating MR
362 transactivation and activity. This process involves enzymes E1, E2, and E3 (130,131). Additionally,
363 acetylation and deacetylation at lysine 677, mediated by histone acetyltransferases (HATs) and
364 histone deacetylases (HDACs), respectively, influence MR transcriptional activity, with HDAC4
365 notably enhancing this activity (132). These post-translational modifications occur on distinct
366 lysine residues and impact MR function, localization, and stability, which have significant
367 implications for cardiovascular diseases (133). It remains to be demonstrated whether similar
368 mechanisms are involved in the regulation of MR during the perinatal period. It can be
369 hypothesized that the transition from an aquatic to a terrestrial environment, which involves
370 changes in ambient tonicity, along with low postnatal sodium intake, given that maternal milk has
371 a low sodium content (134), may involve regulatory mechanisms recruiting RBPs and miRNAs.
372 These mechanisms, associated with osmolality fluctuations, are likely to play a significant role.

373

374 **Conclusion**

375 The MR plays a central role in maintaining electrolyte balance and fluid homeostasis, as well as
376 supporting various developmental processes across different tissues. Its widespread expression in
377 both epithelial and non-epithelial tissues underscores its multifaceted physiological functions,
378 including renal sodium reabsorption and regulation of cardiovascular, immune, and neurological
functions. During development, MR exhibits dynamic, tissue-specific expression patterns that are crucial for the adaptation to extra-uterine life, particularly in organs like the kidney, brain, lung, and heart. These patterns are tightly coordinated with fluctuations in aldosterone levels and environmental changes, like changes in osmolality, reinforcing MR's evolutionary importance in fluid regulation. Loss of MR function, as observed in genetic conditions such as PHA1, highlights its essential role in neonatal health. Proper MR tissue expression during critical developmental periods is vital for maintaining physiological balance. The regulation of MR is complex, involving transcriptional control, RNA processing, and post-translational modifications, which collectively ensure its activity aligns with physiological needs. Recent research indicates that miRNAs and RBPs further modulate MR activity, adding additional layers of control that, when dysregulated, may contribute to disease. Given its importance in development and broad physiological functions, further exploration of MR regulatory mechanisms could lead to targeted therapies for mineralocorticoid-related disorders, especially in preterm neonates and individuals with cardiovascular, renal, or metabolic conditions. Understanding MR ontogeny and function not only advances basic developmental biology but also offers potential clinical benefits for vulnerable populations.
395 **Declaration of interest**

396 All authors have no disclosures related to this work.

397

398 **Funding**

399 This research program received support from Inserm, Université Paris-Saclay, and the Agence

400 Nationale de la Recherche (ANR PERIMIRE 20-CE14-0015). IH has been awarded a Doctoral

401 Fellowship from the ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation

402 (MESRI).

403
406 Fig. 1: Genomic action of the MR in a polarized renal epithelial cell

407 Aldosterone diffuses across the plasma membrane and binds to the MR in the cytoplasm. The
408 hormone-receptor complex then translocates to the nucleus, where it binds to
409 mineralocorticoid response elements (MREs). This binding initiates the recruitment of
410 transcriptional co-regulators and components of the basal transcriptional machinery, leading
411 to the regulation of aldosterone-responsive genes. At the apical membrane, the epithelial
412 sodium channel (ENaC) facilitates sodium entry into the cell, representing the rate-limiting
413 step in sodium reabsorption. Sodium is subsequently transported out of the cell via the
414 basolateral Na+/K+-ATPase pump, whose expression and activity are also enhanced by
415 aldosterone. In the absence of hormonal stimulation, ENaC is targeted for degradation
416 through interaction with the ubiquitin ligase Nedd4-2. A key target gene of aldosterone is
417 *Sgk1*, which contributes to sodium retention by promoting phosphorylation of Nedd4-2
418 through PDK1 activation. Phosphorylated Nedd4-2 dissociates from ENaC, thereby stabilizing
419 the channel at the membrane and enhancing sodium uptake. Additional aldosterone-
420 regulated genes include *KS-WNK1*, *Usp2-45*, *GILZ*, *PER1*, and *NGAL* all contributing to the
421 broader transcriptional response associated with sodium handling and cellular homeostasis.
422
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Sodium reabsorption
<table><caption>Table 1: MR expression during development</caption><thead><tr><td>Tissue</td><td>Onset of MR Expression</td><td>Expression Pattern</td><td>Functional Role / Significance</td><td>References</td></tr></thead><tbody><tr><td>Kidney</td><td>E16-E20 (mice),<br>15-30 GW (humans)</td><td>Biphasic: ↑ late fetal, ↓ at birth, ↑<br>postnatal to adult levels</td><td>Sodium balance, postnatal adaptation; MR defects →<br>pseudohypoaldosteronism (PHA1), sodium wasting</td><td>(Berger et al. 1998;<br>Martinerie et al. 2009)</td></tr><tr><td>Brain</td><td>From E14-E15 (mice); 24-34<br>GW (humans)</td><td>↓ at birth, ↑ postnatal; co-expressed with<br>GR; 11βHSD2 transiently expressed in fetal<br>brain</td><td>Neurodevelopment, cognition &/or memory, stress<br>response, behavior regulation; MR/GR balance</td><td>(Kretz et al. 2001;<br>Noorlander et al. 2006;<br>Galeeva et al. 2010)</td></tr><tr><td>Heart</td><td>From E13.5 (mice)</td><td>Dynamic: early fetal ↑, late fetal ↓,<br>postnatal ↑</td><td>Still being studied; may regulate cardiac development<br>and response to fluid/volume shifts</td><td>(Brown et al. 1996; Reini et<br>al. 2009; Young & Rickard<br>2015)</td></tr><tr><td>Lung</td><td>From E16 (mice); early<br>gestation (humans)</td><td>Stable at birth; expressed in type II<br>pneumocytes</td><td>Essential for alveolar fluid clearance; MR-ENaC<br>interaction supports respiratory transition at birth</td><td>(Helve et al. 2004; Keller-<br>Wood et al. 2005)</td></tr><tr><td>Skin</td><td>Peak at E16.5 (mice)</td><td>Transient expression in fetal life</td><td>Epidermal development; overexpression → postnatal<br>lethality or alopecia; MR KO → mild fetal skin<br>anomalies</td><td>(Sainte Marie et al. 2007b;<br>Boix et al. 2016)</td></tr><tr><td>Gastrointestinal<br>tract</td><td>From E18.5 (mice);<br>early fetal (humans)</td><td>High in colon/duodenum, absent in<br>stomach</td><td>Intestinal sodium regulation</td><td>(Fuller & Verity 1990)</td></tr><tr><td>Retina</td><td>Postnatal D1-D11 (rats)</td><td>Detected in inner retina</td><td>May play a role in retinopathy of prematurity (via<br>aldosterone/AT1R pathway)</td><td>(Golestaneh et al. 2002;<br>Deliyanti et al. 2012)</td></tr><tr><td>Epididymis</td><td>From postnatal D1 to D28<br>(rats)</td><td>Progressive increase</td><td>Role of MR/GR in reproductive tract maturation<br>suspected</td><td>(Gladstones et al. 2012)</td></tr><tr><td>Bone</td><td>From 6 GW (humans),<br>↑ after 12 GW</td><td>Progressive increase</td><td>May contribute to skeletal development</td><td>(Condon et al. 1998)</td></tr></tbody></table>