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Keywords:

  • aldosterone;
  • epidermis;
  • glucocorticoid;
  • hair follicle

Abstract

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

Please cite this paper as: The mineralocorticoid receptor as a novel player in skin biology: beyond the renal horizon? Experimental Dermatology 2010; 19: 100–107.

Abstract:  The mineralocorticoid receptor (MR) and its ligand aldosterone regulate renal sodium reabsorption and blood pressure and much knowledge has been accumulated in MR physiopathology, cellular and molecular targets. In contrast, our understanding of this hormonal system in non-classical targets (heart, blood vessels, neurons, keratinocytes…) is limited, particularly in the mammalian skin. We review here the few available data that point on MR in the skin and that document cutaneous MR expression and function, based on mouse models and very limited observations in humans. Mice that overexpress the MR in the basal epidermal keratinocytes display developmental and post-natal abnormalities of the epidermis and hair follicle, raising exciting new questions regarding skin biology. The MR as a transcription factor may be an unexpected novel player in regulating keratinocyte and hair physiology and pathology. Because its activating ligand also includes glucocorticoids, that are widely used in dermatology, we propose that the MR may be also involved in the side-effects of corticoids, opening novel options for therapeutical intervention.


Nuclear receptors and skin biology

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

Steroid hormones are major regulators of various functions throughout the body, including the skin. Their actions depend on binding to their cognate intracellular receptors. Steroid receptors belong to the nuclear receptor superfamily that are ligand-dependent transcription factors. This family includes the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), the sex steroid receptors for endocrine agents such as androgens, estrogens, and progesterone, the thyroid hormone receptors, the vitamin D receptor (VDR), the retinoic acid receptors (RAR), the peroxisome proliferator-activated receptors (PPAR), and numerous orphan receptors (1–4).

Some of the ligands of nuclear receptors have been shown to modulate keratinocyte growth and wound healing: for example, the thyroid hormones triiodothyronine and thyroxine stimulate epidermal and hair matrix keratinocyte proliferation, skin regeneration and hair growth, with hair follicle (HF) keratinocytes being the primary target as compared to their epidermal counterparts (5–8). Vitamin D hormone metabolites and analogues inhibit the proliferation of cultured keratinocytes and may therefore yield therapeutical benefits in human hyperproliferative skin diseases such as psoriasis (5,7,9,10). Glucocorticoid hormones and retinoic acid derivatives are classical modulators of skin proliferation or differentiation, and are frequently used in dermatology; however, skin atrophy represents a major side-effect of corticosteroid treatments thereby limiting their tolerance (11).

Most, if not all, members of the nuclear receptor family participate in the control of skin homeostasis (3,4,12,13). Their role has been highlighted through genetically modified mouse models. Most of them provided direct information on the involvement of receptor skin functions because gene modification was targeted to the epidermis by using keratin-specific promotors to elicit changes in gene expression. Table 1 illustrates the skin phenotypes observed in such mouse models. Variable abnormalies of epidermis (ranging from hyperplasia to atrophy) and HF (from normal aspect to dysplasic HF and progression towards alopecia) occurred in these mouse models: genetic disruption of the retinoic X receptor (RXR) alpha (14), of the VDR (15,16), knock-out or overexpression of the GR (17,18) and knock-out or inducible overexpression of PPAR alpha (19,20). Targeted knock-out of PPAR gamma in HF epithelial stem cells even induces a type of scarring hair loss in mice that resembles the cicatricial alopecia, lichen planopilaris, in man (21,22). Taken together, these examples document the power and biological importance of members of the nuclear hormone-receptor superfamily as modulators of skin and skin appendage functions.

Table 1.   Skin alterations observed in mice with genetically modified expression of nuclear receptors
Mouse modelAt birthAdult: epidermisAdult: hair follicleReferences
  1. KO, knock-out; receptors, MR, mineralocorticoid; GR, glucocorticoid; RXR, retinoic acid X; PPAR, peroxisome-proliferator-activated receptor.

RXR alpha KO (in keratinocytes)ViableEpidermal hyperplasia Increased basal and utricular keratinocyte proliferation Altered terminal differentiation Skin inflammatory infiltratesImpaired anagen initiation Progressive alopecia Destruction of HF architecture; dermal cysts(14)
Vit D receptor KOViable (normal skin at birth)Reduced epidermal differentiation (first month of life)Progressive alopecia; disruption of HF structure(15,16)
GR KO (in keratinocytes)Incomplete epidermal stratification Reduced terminal differentiation Compromised skin barrier functionN.d (because of early post-natal death)N.d (because of early post-natal death)(17)
GR overexpression (in keratinocytes)Severe skin atrophy HFs underdeveloped, dysplasic Early post-natal deathImpaired hyperplastic and inflammatory response to the tumor promoting agent TPAImpaired entry into anagen in response to the tumor promoting agent TPA(18)
PPAR alpha KOViable Delayed formation of stratum corneumThinner stratum granulosum Focal parakeratosis in stratum corneumNormal(19)
Inducible PPAR alpha overexpression (in keratinocytes)Thin epidermis Fewer HFs Early post-natal death(suckling problems)Increased differentiation Decreased proliferationThin hair coat(20)
MR KO (non-targeted)Early post-natal deathN.d (because of early post-natal death)N.d (because of early post-natal death)(24)
Inducible MR overexpression (in keratinocytes)Skin atrophy Premature barrier function establishment Increased apoptosis Early post-natal deathNormal epidermisProgressive alopecia Dysplasic HF Dermal cysts No inflammation(26)

Although it has long been reported that the MR, another key member of this nuclear receptor superfamily, is expressed in human skin (23), very little information has been available so far on the function of MR and its best-studied and classical ligand, aldosterone, in mammalian skin biology. In mice, constitutive MR knock-out is not lethal before birth, indicating that this receptor is dispensable for embryonic development, thereby suggesting that other receptors including the GR or other members of the nuclear receptor family can at least partially compensate for the loss of MR (24). However, the MR knock-out mice die a few days after birth, apparently from uncontrolled renal salt loss (25), which precludes obtaining information on the consequence of post-natal MR ablation, particularly in the skin. The skin-targeted knock-out of MR (avoiding mortality due to altered salt balance) would be of great help to get more insights into the function of this receptor.

Therefore, we have recently developed a mouse model with conditional overexpression of the MR, restricted to basal keratinocytes (keratin 5 promotor, tet system, referred as K5-MR mice). Interestingly, K5-MR mice exhibit developmental and post-natal abnormalities of the epidermis and HF (26) (Fig. 1). End-gestation embryos had epidermal hypoplasia with increased apoptosis, absence of eyelids and reduced number of HFs; pups were alive just after birth, but presented with severe skin atrophy that compromized survival. When MR expression was initiated after birth to overcome perinatal mortality, DT mice developed progressive alopecia with dysplasic HFs leading to cysts surrounding the hair shaft; in contrast the interfollicular epidermis appeared normal. These results show that the MR is indeed involved in epidermal and HF growth and may constitute an important factor regulating development thereby raising many exciting and intriguing questions regarding the decisive role of the MR in skin and hair biology.

image

Figure 1.  Morphological abnormalities of the epidermis (a,b) and hair follicles (c, d) occurring in mice overexpressing the mineralocorticoid receptor in keratinocytes (26) referred as K5-MR mice. Note the thin and flat epidermis in K5-MR embryos (b) as compared to controls (a). Adult K5-MR mice exhibit dystrophic hair follicles and cysts [(d) compared to (c), normal littermates] leading to alopecia.

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These findings when viewed in the context of the tremendous progress in the fields of MR physiology and pharmacology (27–29) strongly encourage one to explore the molecular mechanisms of action and effects of MR-mediated signalling in the skin and the HF, and to consider new options for therapeutic interventions in clinical dermatology via targeting of this receptor (26). On this background, the current viewpoint essay synthesizes the few available facts on intracutaneous MR expression and function that emerge from studies on mouse models and human diseases (26), and develops novel concepts on the potential role of MR-mediated signalling in skin physiology, pathophysiology, pharmacology and toxicology.

The MR/aldosterone system

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

The 450-kb human MR gene (NR3C2) exhibits 10 exons, encoding for a 984 amino-acid protein. The protein has a general organization close to that of other nuclear receptors, consisting of a large N-terminal domain, a central DNA-binding domain with high homology with the corresponding regions of the GR, the androgen and the progesterone receptors, and a ligand-binding domain that has been crystallized recently (30). Detailed review of the structure and function of the MR is provided in excellent recent reviews (27–29,31,32).

MR ligands include the mineralocorticoid hormone aldosterone as well as glucocorticoids (27,29,31). The MR has similar and high affinity (0.1–1 nM) for aldosterone (aldo) and for glucocorticoid hormones (gluco). Glucocorticoids largely prevail in the plasma: they are present in 100–1000 fold excess over aldosterone. Permanent occupancy of the MR by glucocorticoids is prevented by the MR-protector enzyme 11 beta hydroxysteroid dehydrogenase type 2 (HSD2), the enzyme that metabolizes glucocorticoids into inactive derivatives – for instance cortisol into cortisone – in humans (Fig. 2). Depending on the colocalization (or proportion) of MR and HSD2, the MR will be predominantly occupied by aldosterone or glucocorticoids; this is important, as it will favor formation of aldo-MR or gluco-MR complexes (Fig. 2), that have been shown to display distinct transcriptional activities (and probably different target genes in vivo) (33).

image

Figure 2.  Aldosterone target cells express both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The MR may be occupied by aldosterone (kidney cells) and also by glucocorticoids (gluco, that are much more abundant than aldo in the plasma) in cells with low activity of the glucocorticoid-metabolizing enzyme 11 beta hydroxysteroid dehydrogenase HSD2, leading to distinct transcriptional regulations (aldo-MR versus gluco-MR).

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Upon agonist binding, MR chaperone proteins like the heat shock protein HSP90 dissociate from MR, and the receptor is activated (27–29,31,32). The hormone-receptor complexes bind to glucocorticoid response elements (GREs) within the promotor region of early aldosterone-regulated genes to modulate their transcription. There are no specific mineralocorticoid-specific response elements, and mineralocorticoid, glucocorticoid, androgen as well as progesterone receptors bind to the same GREs (28,32). Of note, transcriptional regulation does not necessarily require direct interactions with GREs, and can be also mediated by protein–protein contacts, as shown for the GR (34).

Regulation of transcription involves binding of regulatory proteins as coactivators or corepressors, that are usually widely expressed among tissues and that are common to several nuclear receptors; the characterization of coregulators that specifically regulate MR activity would represent a great progress in understanding MR actions. Transcriptional activation requires dimer formation, either in the form of homodimers (MR-MR) or heterodimers with the GR (MR-GR). The relative proportion of homo/heterodimers (each bound to aldo or gluco) provides further flexibility to transcriptional regulations. While experimental clues for this flexilibity have been (partly) shown in transfected cell models, it remains difficult to identify in vivo in native cells. However, the relative proportion of MR and GR is certainly important to determine their hormonal activation within a selected tissue/cell type (35).

Control of sodium reabsorption in the kidney by MR and aldosterone

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

Aldosterone plays a major role in the control of blood pressure and extracellular volume homeostasis through its capacity to enhance sodium reabsorption in the distal parts of the nephron (31,36,37). Activation of the renal MR triggers transcription (or repression) of several genes (early response genes) that ultimately result in an increase in the activity and number of sodium transporters or channels (31,36,37).

The classical MR antagonist spironolactone and its metabolite canrenoate have been used for decades to limit the hypertension due to aldosterone-related increase in renal sodium reabsorption (38). Their use has been limited by their relative lack of MR specificity: spironolactone for instance is a weak androgen antagonist, inducing development of gynecomastia in males (39,40). The recently developed MR antagonist eplerenone exhibits reduced affinity for the MR, but does not bind to other steroid hormone receptors and has proved to be efficient and selective in MR blockade (39,40).

MR in non-epithelial cells

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

It constituted an important paradigm shift when it became evident that the MR/aldosterone/gluco system is also found in many extrarenal organs and their specific cellular constituents, such as cardiomyocytes, endothelial and smooth muscle cells, neurons, adipocytes and keratinocytes (32,41). The downstream signalling cascades are still largely unexplored and great efforts are made to understand the role of MR in these so-called non-classical aldosterone/MR target tissues. Most of these non-classical target tissues lack HSD2, so that the MR should bind essentially glucocorticoids.

Inappropriate MR activation may lead to severe cardiovascular pathologies including hypertension, and cardiac failure or arythmias independent of the hypertensive effect (42,43). Large multicentric trials (RALES, EPHESUS) have shown that spironolactone or eplerenone treatment of patients with heart failure (in addition to standard therapy) provides a substantial benefit, in terms of morbidity and mortality, leading to an extension of their status as prescription drugs for the treatment of cardiac insufficiency (42,43). The mechanisms underlying beneficial effects of MR antagonists are far from being fully understood. Indeed these drugs appear to be efficient in face of hyperaldosteronism, but also in situations where plasma aldosterone levels are normal or low. If it is assumed that spironolactone/eplerenone counteract MR overactivation, then it is necessary to search for other ligands in addition to aldosterone that may act also as endogenous agonists or modulators of this receptor in mediating the specific signalling-dependent MR responses. Glucocorticoids may constitute such endogenous ‘illegitimate’ MR ligands even at normal baseline levels or at least after stress-related and circadian peak-associated altered and enhanced secretion rates (44). Along this line, a recent study showed that higher serum levels of cortisol and aldosterone are indeed independent, complementary, and incremental predictors of all-cause mortality risk in patients with chronic heart failure (45).

Neurons also express the MR, where it may be involved in modulating mood and anxiety (46). Recent data show that the MR is also involved in adipocyte metabolism (47) and MR antagonism appears to exert beneficial effects in blocking some obesity-associated changes (48). This observation may lead to the development of novel pharmacological approaches for the treatment of metabolic syndromes and disorders.

Aldosterone and MR in the skin: from frogs to humans

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

Landmark studies dedicated to the understanding of aldosterone action were performed on frog skin, an epithelium that regulates body sodium because it can reabsorb sodium chloride and water from the external milieu, allowing adaptation of frogs to dry versus wet environment (49–51). Aldosterone is also involved in the moulting process in amphibians (52), probably via exerting some – still poorly characterized – effects on skin differentiation. MR mRNA expression has been documented in mouse skin (26,53).

Interestingly, and of major note in the current context, human skin has retained MR expression (23,54), although it seems to have lost the capacity to regulate sodium homeostasis (or is at least far removed in its efficacy of doing so, compared to its amphibian ancestors). Besides in the human sweat gland duct, where aldosterone regulates sweat ionic composition in particular during prolonged exercise and heat acclimatization (55), MR is also found in the epidermis, the sebaceous glands and HF of human skin (23). The question, therefore, arises whether the intraepidermal or intrafollicular expression of MR has to be considered as merely vestigial – or whether it is conceivable that MR has an important, as yet under-explored and obscure functional role in mammalian skin physiology. To our knowledge, there are no histological studies dedicated to detailed analyses of skin or hair morphology in human diseases with chronic alterations of plasma aldosterone levels, such as primary aldosteronism (Conn and related syndromes) or global corticosteroid secretion defects (as Addison’s disease). It should also be noted that these diseases often include a large series of endocrine disorders that preclude to draw clear relationships between skin/hair abnormalities and aldosterone levels.

MR signalling in the skin: the MR/ENaC connection?

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

Nothing is known about MR downstream signalling in the skin. Candidate targets may include the ‘classical’ aldosterone-regulated genes of kidney cells, such as ion channels and their regulatory proteins, tight junctions proteins or distinct signalling networks that remain to be investigated. Of interest, the traditional notion that mineralocorticoid action converges to up-regulate ion channels and transporters in epithelial cells only may be extended to non-classical targets such as cardiomyocytes. Indeed recent reports point to aldosterone/MR ion channel remodelling as a key and perhaps causative event in cardiovascular physiopathologic actions of MR/aldosterone. Patch-clamp analyses of mouse cardiomyocytes showed that the amplitude of L-type calcium currents correlates with plasma aldosterone levels; such regulation has important consequences for excitation–contraction coupling and, potentially, for other calcium-regulated functions in cardiomyocytes (56). In addition cardiomyocytes of mice overexpressing the MR have increased action potential duration, downregulation of outward potassium currents and upregulation of calcium currents, resulting in severe ventricular arrhythmias (57).

It is conceivable that aldosterone/MR also modifies sodium, potassium or calcium currents in keratinocytes, leading to altered epidermal ion homeostasis. This hypothesis is based on the findings that keratinocytes express epithelial sodium channel (ENaC) (58–60), and that differentiation of cultured human keratinocytes is associated with enhanced beta ENaC expression (58). Keratinocytes cultured on permeable filters did not exhibit significant transepithelial sodium transport from one side of the filter towards the opposite one; however, patch-clamp recordings of keratinocytes occasionally showed whole cell currents with properties similar to those of ENaC (58). It was also demonstrated that ENaC inhibitors impaired the formation of domes in confluent keratinocyte monolayers (58).

Taken together, these findings indicate an –as yet ill-defined-, but actually significant role of ENaC in the epidermal physiology and homeostasis. Interestingly, the beta subunit of ENaC has been identified in the transcriptome of human keratinocytes treated with the glucocorticoid dexamethasone (61). The epidermis also expresses high levels of some serine proteases belonging to signalling cascades that modify ENaC activity in aldosterone-sensitive epithelia. Matriptase (also named MT/SP1 or Cap 3) cleaves the inactive form of prostasin (also named Cap1 or PRSS8) into an active protease that activates ENaC, as shown in renal cells and in the Xenopus Oocyte expression system (62,63). Interestingly, genetic disruption of the ENaC-activating serine-protease CAP1 leads to severe impairement of skin barrier permeability (64); matriptase knock-out also results in impaired epidermal barrier function (65). Both mouse models present early post-natal mortality, reddish and wrinkled skin at birth, immature HFs and enlarged corneocytes. Thus, although it is promising that several molecules closely associated with aldosterone signalling are expressed in the skin, the issue whether ENaC may be regulated following MR activation in keratinocytes has yet to be addressed in future investigations of skin MR function.

What is the ligand of MR in mammalian skin?

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

The documented activity of the glucocorticoid-metabolizing enzyme HSD2 in the human skin is very low and has been claimed to be largely restricted to the sweat glands (23,66). However, normal rat skin engages in steroidogenesis (67) and CRH stimulates corticosterone production in human dermal fibroblasts in vitro (68,69).

It is thus theoretically conceivable that glucocorticoids (rather than aldosterone) could be the main physiological agonists of the MR in the epidermis and HF. Of importance, the glucocorticoid-mediated MR transactivation activity may differ from aldo-MR activity. In view of the epidermal atrophy observed in mice with MR overexpression (K5-MR model) (26), we propose that skin atrophy could depend on inappropriate/excessive glucocorticoid-stimulated MR activity. This situation may be reminiscent of the clinical observations of glucocorticoid-induced skin atrophy. We hypothesize that such adverse effects of glucocorticoids may be due to their excessive binding to the MR. This may have major pharmacological consequences, as blockade of MR occupancy could, then, become an efficient novel strategy for attenuating glucocorticoid-induced skin atrophy.

The HF as a source of corticosteroids: a novel autocrine system?

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

The HF is both a source and a target of many hormones and metabolizes such agents thereby enabling auto- and paracrine signalling in the skin (70). Concerning corticosteroids, evidence has been provided for production of cortisol by the human HF (71); rat skin also exhibits capacity for steroidogenesis as it can produce 11-deoxycorticosterone that may be converted into corticosterone and 11-dehydrocorticosterone (67); however, no local synthesis of aldosterone was apparent in these experiments. These observations raise the question of the role of this local endocrine loop in skin functions and encourage one to explore whether mammalian skin is actually also capable of synthesizing aldosterone.

MR needs transcriptional coregulators: a role for hairless?

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

As other nuclear receptors the activity of the MR may be modulated by coactivators/ corepressors, i.e. molecules that are directly recruited in the nucleus to enhance or reduce transcriptional activity and thus gene expression. Coactivators/corepressors are physiological regulators that may have different cell-specific regulatory functions although they are usually considered as ubiquitous. Most of them can interact in vitro with several receptors (72) and some of them regulate specifically the MR, as PIAS1 (Protein Inhibitor of Activated Signal transducer and activator of transcription) and ELL (Eleven-nineteen Lysin-rich Leukemia) (32). Of note, there is a complete lack of information on putative skin-specific MR coregulators. Here, the proposed role of hairless as an original coregulator (73) deserves special mentioning, as it is mainly expressed the skin. Corepressor activity of hairless has been demonstrated on thyroid receptor (74), on VRD (75) and on RXR, while retinoic acid receptor RARα or GR activities are unaffected (75); effect of hairless on MR has not been evaluated. Mutations of the hairless gene result in congenital hair loss in mice and humans. Hairless mice develop very early (day 14 PN) alopecia in the periorbital region and forelimbs, up to generalized alopecia at day 21 PN, accompanied by massive premature apoptosis (76). This phenotype clearly differs from the phenotype observed in mice overexpressing the MR in keratinocytes (K5-MR mice), that present with delayed alopecia (apparent only after 3–4 months) initially located in the dorsal part of the neck and the ventral region (26). In addition, we have also found that prenatal induction of MR expression in the skin was lethal while hairless mice survive the embryonic period. Therefore, quite distinct mechanisms likely trigger alopecia in these two models. Whether the hairless protein could regulate the MR remain unknown, however, and certainly deserves future attentions.

Challenges in skin research: is MR involved in epidermal or hair pathophysiology?

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References

Investigations of MR signalling in skin could benefit from transcriptomic/proteomic analyses of the epidermis and the HF of mice overexpressing the MR using the well documented K5-MR model, compared to skin from animals challenged with MR agonists and antagonists. From such an approach it is expected to point out how these signalling networks are orchestrated and to increase our knowledge on MR functions that may contribute to regulate skin and hair biology by identifying and investigating the specific endogenous mediators and molecular mechanisms that could serve as novel pharmaceutical targets to modify epidermal differentiation or hair/fur growth as well as the development of other skin appendages such as feathers.

The role of MR in human skin pathophysiology has not yet been addressed systematically. If glucocorticoid-induced epidermal atrophy is in some way related to inappropriate MR occupancy, it is tempting to propose concomitant local administration of MR antagonists for instance during local or systemic corticoid treatments to limit the atrophy of the epidermis (ongoing clinical trial). This would represent a major new strategy to limit the adverse effects of glucocorticoids, inasmuch as MR antagonists also exert anti-inflammatory actions, at least in certain circumstances. For instance, rats treated with deoxycorticosterone acetate and salt supplementation exhibit cardiac fibrosis, vascular remodelling and enhanced expression of inflammation markers that can be fully prevented by MR antagonism (77).

MR antagonism may also interfere with hair growth defects. Some publications reported successful reversal of androgenic alopecia in some patients treated with the MR antagonist spironolactone: this drug is used to treat hirsutism and occasionally androgenetic alopecia, which has been classically attributed to spironolactone’s antagonism of androgen receptors and its interference with steroidogenesis (5,78,79). It would be interesting to test whether the more specific MR antagonist eplerenone has any effect on hair growth. Moreover it was recently reported that patients with androgenetic alopecia exhibit higher blood pressure and plasma aldosterone levels than healthy controls (80); such observation is encouraging to stimulate efforts to define the role of the MR/aldosterone system in hair biology. No report on skin abnormalities has been highlighted, perhaps because they have not been looked at.

If the use of MR antagonists appears beneficial under some circumstances, our – as yet poor – knowledge of the pharmacokinetics of these drugs in the skin and its appendages must be greatly improved. In particular, local application (topical) versus systemic administration may prove to be more efficient.

In conclusion, the recent developments in our understanding of the specific actions of the epidermal MR promises important new insights into the regulation of skin physiology and pathophysiology by this specific nuclear receptor, its endogenous ligands and signalling modulators. It is to be expected that these insights will help to develop innovative therapeutic strategies in the management of mineralocorticoid-related skin diseases and disorders.

References

  1. Top of page
  2. Abstract
  3. Nuclear receptors and skin biology
  4. The MR/aldosterone system
  5. Control of sodium reabsorption in the kidney by MR and aldosterone
  6. MR in non-epithelial cells
  7. Aldosterone and MR in the skin: from frogs to humans
  8. MR signalling in the skin: the MR/ENaC connection?
  9. What is the ligand of MR in mammalian skin?
  10. The HF as a source of corticosteroids: a novel autocrine system?
  11. MR needs transcriptional coregulators: a role for hairless?
  12. Challenges in skin research: is MR involved in epidermal or hair pathophysiology?
  13. References