Tissue-specific modulation of mineralocorticoid receptor function by 11β-hydroxysteroid...

Molecular and Cellular Endocrinology 350 (2012) 168–186

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Molecular and Cellular Endocrinology

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Tissue-specific modulation of mineralocorticoid receptor functionby 11b-hydroxysteroid dehydrogenases: An overview

Alex Odermatt ⇑, Denise V. KratschmarDivision of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland

a r t i c l e i n f o a b s t r a c t

Article history:Available online 22 July 2011

Keywords:11b-Hydroxysteroid dehydrogenaseMineralocorticoid receptorGlucocorticoid receptorCortisolAldosterone

0303-7207/$ - see front matter � 2011 Elsevier Irelandoi:10.1016/j.mce.2011.07.020

⇑ Corresponding author. Tel.: +41 61 267 1530; faxE-mail address: [email protected] (A. Oder

In the last decade significant progress has been made in the understanding of mineralocorticoid receptor(MR) function and its implications for physiology and disease. The knowledge on the essential role of MRin the regulation of electrolyte concentrations and blood pressure has been significantly extended, andthe relevance of excessive MR activation in promoting inflammation, fibrosis and heart disease as wellas its role in modulating neuronal cell viability and brain function is now widely recognized. Despite con-siderable progress, the mechanisms of MR function in various cell-types are still poorly understood. Keymodulators of MR function include the glucocorticoid receptor (GR), which may affect MR function byformation of heterodimers and by differential genomic and non-genomic responses on gene expression,and 11b-hydroxysteroid dehydrogenases (11b-HSDs), which determine the availability of intracellularconcentrations of active glucocorticoids. In this review we attempted to provide an overview of theknowledge on MR expression with regard to the presence or absence of GR, 11b-HSD2 and 11b-HSD1/hexose-6-phosphate dehydrogenase (H6PDH) in various tissues and cell types. The consequences ofcell-specific differences in the coexpression of MR with these proteins need to be further investigatedin order to understand the role of this receptor in a given tissue as well as its systemic impact.

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Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1682. Kidney. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1693. Gastrointestinal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1734. Adrenals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1745. Immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1746. Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1757. Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1768. Adipose tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1779. Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17810. Skeletal muscle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18011. Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18112. Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

Disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

1. Introduction

The use of complementary DNA of the glucocorticoid receptor(GR, systematic name NR3C1) and low-stringency hybridization

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by Arizza et al. led to the identification of a cDNA coding for a107 kDa polypeptide, which was functionally characterized asmineralocorticoid receptor (MR) (Arriza et al., 1987). The MR isalso known as aldosterone receptor and under the systematicname NR3C2 (Nuclear Receptor subfamily 3, group C, member 2).MR and GR share about 90% amino acid homology in their DNA

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A. Odermatt, D.V. Kratschmar / Molecular and Cellular Endocrinology 350 (2012) 168–186 169

binding domain (DBD) but only about 50% in their ligand bindingdomain (LBD). Evolutionary analyses suggested that MR and GRevolved from a common ancestor and that the MR was the firstto diverge from the ancient receptor gene (Kassahn et al., 2011;Hu and Funder, 2006). Importantly, MR existed well before aldo-sterone appeared in evolution, whereas GR seems to have appearedlater in evolution. This may explain the rather broad substratespecificity of MR, compared with the more selective GR. WhereasMR binds aldosterone, 11-deoxycorticosterone, corticosterone,cortisol and progesterone with similarly high affinities and Kd val-ues between 0.5 and 3 nM, GR shows a higher selectivity to cortisoland corticosterone with Kd values of 20–70 nM (Arriza et al., 1987;Funder and Myles, 1996; Krozowski and Funder, 1983).

The cloning of MR allowed its exact localization in various tis-sues and identification of specific cell types expressing this recep-tor. The subsequent cloning of 11b-hydroxysteroid dehydrogenasetype 1 (11b-HSD1) (Agarwal et al., 1989) and 11b-HSD2 (Agarwalet al., 1994; Albiston et al., 1994), and determination of their tis-sue- and cell-specific expression patterns, then allowed a compar-ison with the expression pattern of MR and GR. It soon becameclear that MR is not only expressed in cells where 11b-HSD2 actsas a ‘‘gate-keeper’’ to protect MR from high concentrations of glu-cocorticoids and rendering specificity for aldosterone (Edwardset al., 1988; Funder et al., 1988). As discussed below, the MR playsan important role in cells coexpressing 11b-HSD1, including mac-rophages, preadipocytes/adipocytes, osteoblasts/osteoclasts, andmicroglia cells, by modulating cell proliferation and inflammatoryresponse. Thus, the classic view of mineralocorticoid target tissues,where MR function is thought to be strictly regulated by aldoste-rone, has to be reconsidered.

2. Kidney

The kidney is considered as the classical mineralocorticoid tar-get tissue. High-affinity aldosterone binding sites, corresponding toMRs, and lower affinity glucocorticoid binding sites, correspondingto GRa, were characterized in rat kidney almost 40 years ago(Funder et al., 1972, 1973). Aldosterone-induced renal epithelialsodium transport was found to be dependent on a nuclear transac-tivating receptor that was later identified as the MR (Arriza et al.,1987; Porter et al., 1964). The MR has similar high binding affini-ties for aldosterone, progesterone, 11-deoxycorticosterone, corti-costerone and cortisol, with Kd values between 0.5 and 3 nM(Arriza et al., 1987; Krozowski and Funder, 1983), whereas theGR shows higher ligand selectivity but approximately 20-fold low-er affinity for cortisol and very weak affinity for aldosterone (Kd

Fig. 1. Schematic overview of mineralocorticoid receptor (MR) and glucocorticoid rdehydrogenases (11b-HSDs) and hexose-6-phosphate dehydrogenase (H6PDH) in cells o

about 500 nM). The identification of 11b-HSD2 as a ‘‘gate-keeper’’to protect MR from active 11b-hydroxyglucocorticoids (cortisol inhumans, corticosterone in rodents) that are present in plasma atabout 1000-fold higher concentrations than aldosterone providedan explanation for the specificity of this receptor towards aldoste-rone (Edwards et al., 1988; Funder et al., 1988) (Fig. 1).

Investigation of the expression of MRs in human, rat and rabbitkidney revealed colocalization with 11b-HSD2 in the distal tubulesand cortical collecting ducts (Table 1) (Ackermann et al., 2010;Bostanjoglo et al., 1998; Farman and Bonvalet, 1983, 1985; Farmanet al., 1991; Lombes et al., 1990). 11b-HSD2 is an endoplasmicreticulum (ER) resident enzyme with its catalytic domain facingthe cytoplasm (Naray-Fejes-Toth and Fejes-Toth, 1996, 1998;Odermatt et al., 1999). Experiments with cultured cells expressingrecombinant MR and 11b-HSD2 revealed a tethering of the receptorto 11b-HSD2 at the ER membrane in the absence of steroid hor-mones as well as in the presence of low concentrations of cortisol(Odermatt et al., 2001). In contrast, low concentrations of aldoste-rone were efficient to induce almost complete translocation ofMRs into the nucleus and to stimulate the expression of the GR/MR-dependent reporter gene MMTV-lacZ. High concentrations ofcortisol or corticosterone (>250 nM) led to the activation of MR,probably as a result of saturation of 11b-HSD2. These experimentssuggested a close proximity of MR and 11b-HSD2, allowing the latterto efficiently inactivate cortisol at the site of the receptor and pre-vent binding of the active glucocorticoid at low concentrations, i.e.at the nadir of circadian rhythm.

In a recent study, Ackermann et al. used MR- and GR-specificantibodies to determine the localization of the receptors in kidneysof rats with altered aldosterone and corticosterone levels(Ackermann et al., 2010). Immunohistochemistry detected MRand GR in the nuclei of the aldosterone-sensitive distal nephron,including cells of the late distal convoluted tubule, connectingtubule and collecting duct. These cells also express high levels of11b-HSD2. In addition, MR and GR expression was found in thethick ascending limb and in intercalated cells, where 11b-HSD2is absent. It was suggested that MR in intercalated cells may beinvolved in proton secretion, thereby playing an essential role inacid/base regulation. The role of MR in these cell types remainsto be elucidated. In rats on a high-salt diet, which is known to low-er plasma aldosterone, MR localization to the nuclei in cells of thealdosterone-sensitive distal nephron was unchanged, whereas GRwas found exclusively in the cytoplasm. The actual diet-inducedchanges in circulating aldosterone and corticosterone levels,however, have not been determined in this study. It seems unlikelythat altered aldosterone levels affected GR but not MR localization.The time point where the samples have been taken is not indicated,

eceptor (GR) regulation with respect to the expression of 11b-hydroxysteroidf renal proximal tubules (PCT) and cortical collecting ducts (CCD).

Table 1Expression of mRNA and protein of MR, GR, 11b-HSD2, 11b-HSD1 and H6PDH in kidney cells.

Kidney Protein RNA

Whole kidney MRGR11b-HSD1 + (Gomez-Sanchez et al., 2008) + (Moore et al., 2000)

+ (Gomez-Sanchez et al., 2008)11b-HSD2H6PDH + (Gomez-Sanchez et al., 2008) + (Gomez-Sanchez et al., 2008)

Glomerulus MR � (Farman et al., 1991) � (Ackermann et al., 2010)� (Roland et al., 1995)

GR + (Farman et al., 1991)+ (Ackermann et al., 2010)

+ Ackermann et al., 2010)

11b-HSD1 � (Gong et al., 2008)11b-HSD2H6PDH + (Gomez-Sanchez et al., 2008)

Proximal tubule (PT) cells MR � (Fukushima et al., 1991)� (Farman et al., 1991)

GR + (Fukushima et al., 1991)+ (Ackermann et al., 2010)

++ (Roland et al., 1995)

11b-HSD1 + (Brereton et al., 2001) + (Roland et al., 1995)11b-HSD2 � (Roland et al., 1995)H6PDH + (Gomez-Sanchez et al., 2008)

Proximal convoluted tubule (PCT) MR � (Farman et al., 1991) � (Ackermann et al., 2010)� (Roland et al., 1995)

GR + (Ackermann et al., 2010) + (Ackermann et al., 2010)11b-HSD1 + (Roland et al., 1995)11b-HSD2 � (Roland et al., 1995)H6PDH + (Tanahashi and Hori, 1980)

++ (Gomez-Sanchez et al., 2008)

P1 MRGR11b-HSD111b-HSD2 � (Roland et al., 1995)H6PDH +/� (Tanahashi and Hori, 1980)

+/� (Gomez-Sanchez et al., 2008)

P2 MRGR11b-HSD111b-HSD2 � (Roland et al., 1995)H6PDH + (Tanahashi and Hori, 1980)

+ (Gomez-Sanchez et al., 2008)

P3 MRGR11b-HSD1 + (Gong et al., 2008)11b-HSD2 � (Roland et al., 1995)H6PDH ++ (Tanahashi and Hori, 1980)


Proximal straight tubules (PST) MR � (Farman et al., 1991) � (Ackermann et al., 2010)� (Roland et al., 1995)

GR � (Farman et al., 1991) + (Ackermann et al., 2010)11b-HSD111b-HSD2 � (Roland et al., 1995)H6PDH + (Gomez-Sanchez et al., 2008)

Cortex MR + (Lombes et al., 1995) + (Lombes et al., 1995)+ (Roland et al., 1995)

GR + (Ackermann et al., 2010) ++ (Roland et al., 1995)11b-HSD111b-HSD2 + (Ackermann et al., 2010) + (Roland et al., 1995)H6PDH + (Tanahashi and Hori, 1980)

+ (Gomez-Sanchez et al., 2008)

Aldosterone-sensitive distal nephron (ASDN) MR + (Ackermann et al., 2010)+ (Lombes et al., 1995)

+ (Lombes et al., 1995)

GR + (Ackermann et al., 2010)11b-HSD111b-HSD2 ++ (Ackermann et al., 2010)H6PDH + (Gomez-Sanchez et al., 2008)

Macula densa MR + (Bostanjoglo et al., 1998)GR11b-HSD1 + (Gomez-Sanchez et al., 2008)11b-HSD2H6PDH + (Gomez-Sanchez et al., 2008)

170 A. Odermatt, D.V. Kratschmar / Molecular and Cellular Endocrinology 350 (2012) 168–186

Table 1 (continued)

Kidney Protein RNA

Connecting tubule (CNT) MR + (Ackermann et al., 2010)+ (Farman et al., 1991)+ (Bostanjoglo et al., 1998)+ (Gomez-Sanchez et al., 2006)

+ (Ackermann et al., 2010)

GR + (Ackermann et al., 2010)+ (Farman et al., 1991)


11b-HSD111b-HSD2 ++ (Ackermann et al., 2010)

++ (Naray-Fejes-Toth and Fejes-Toth, 2007)++ (Bostanjoglo et al., 1998)

++ (Bostanjoglo et al., 1998)

H6PDH + (Gomez-Sanchez et al., 2008)

Distal convoluted tubules (DCT) MR + (Farman et al., 1991)+ (Bostanjoglo et al., 1998)+ (Fukushima et al., 1991)+ (Ackermann et al., 2010)+ (Gomez-Sanchez et al., 2006)

+ (Ackermann et al., 2010)+ (Uhrenholt et al., 2003)++ (Roland et al., 1995)

GR + (Farman et al., 1991)+ (Ackermann et al., 2010)

+ (Roland et al., 1995)+ (Ackermann et al., 2010)

11b-HSD1 � (Roland et al., 1995)11b-HSD2 + (Naray-Fejes-Toth and Fejes-Toth, 2007)

+ (Bostanjoglo et al., 1998)+ (Ackermann et al., 2010)+ (Brereton et al., 2001)

� (Bostanjoglo et al., 1998)


Segment-specific cells of late distal convoluted tubule (DCT2) MR + (Ackermann et al., 2010)+ (Farman et al., 1991)+ (Bostanjoglo et al., 1998)

+ (Ackermann et al., 2010)+ (Roland et al., 1995)

GR + (Farman et al., 1991)+/� (Ackermann et al., 2010)

11b-HSD1 � (Roland et al., 1995)11b-HSD2 ++ (Ackermann et al., 2010)

++ (Bostanjoglo et al., 1998)++ (Bostanjoglo et al., 1998)++ (Roland et al., 1995)


Collecting duct (CCD). MR + (Ackermann et al., 2010)+ (Bostanjoglo et al., 1998)+ (Gomez-Sanchez et al., 2006)+ (Farman et al., 1991)

++ (Ackermann et al., 2010)++ (Arriza et al., 1988)++ (Roland et al., 1995)++ (Uhrenholt et al., 2003)

GR + (Ackermann et al., 2010) + (Arriza et al., 1988)+ (Roland et al., 1995)+ (Ackermann et al., 2010)

11b-HSD1 � (Gomez-Sanchez et al., 2008)11b-HSD2 ++ (Ackermann et al., 2010)

++ (Naray-Fejes-Toth and Fejes-Toth, 2007)++ (Bostanjoglo et al., 1998)++ (Sinclair et al., 2007)++ (Brereton et al., 2001)++ (Sinclair et al., 2007)

++ (Bostanjoglo et al., 1998)


Intercalated cells (IC) MR � (Farman et al., 1991)� (Bostanjoglo et al., 1998)+ (Ackermann et al., 2010)

GR + (Ackermann et al., 2010)11b-HSD111b-HSD2 + (Ackermann et al., 2010)H6PDH + (Gomez-Sanchez et al., 2008)

Interstitial cells of the medulla MRGR11b-HSD1 + (Brereton et al., 2001)

+ (Gong et al., 2008)+ (Gomez-Sanchez et al., 2008)

11b-HSD2H6PDH �/(+) (Gomez-Sanchez et al., 2008)

Inner medulla MR + (Roland et al., 1995)GR + (Sheppard and Funder, 1987) + (Roland et al., 1995)11b-HSD1 + (Roland et al., 1995)11b-HSD2H6PDH ++ (Tanahashi and Hori, 1980)


Inner medullary collecting ducts (IMCD) MR + (Farman et al., 1991) + (Ackermann et al., 2010)GR + (Farman et al., 1991) + (Ackermann et al., 2010)11b-HSD111b-HSD2 + (Bostanjoglo et al., 1998) + (Bostanjoglo et al., 1998)

(continued on next page)


Table 1 (continued)

Kidney Protein RNA


Outer medullary collecting ducts (OMCD) MR + (Farman et al., 1991) + (Ackermann et al., 2010)+ (Roland et al., 1995)

GR + (Farman et al., 1991) + (Ackermann et al., 2010)11b-HSD111b-HSD2 ++ (Bostanjoglo et al., 1998) ++ (Bostanjoglo et al., 1998)H6PDH + (Gomez-Sanchez et al., 2008)

Thick ascending limb (TAL) MR + (Ackermann et al., 2010)GR + (Ackermann et al., 2010)11b-HSD111b-HSD2 � (Bostanjoglo et al., 1998) � (Bostanjoglo et al., 1998)H6PDH + (Gomez-Sanchez et al., 2008)

Outer medullary thick ascending limbs (OMTAL MR ++ (Farman et al., 1991) + (Ackermann et al., 2010)GR + (Farman et al., 1991) + (Ackermann et al., 2010)11b-HSD111b-HSD2H6PDH + (Gomez-Sanchez et al., 2008)

Medullary thick ascending limbs (MTAL) MR + (Farman et al., 1991)GR ++ (Farman et al., 1991)11b-HSD111b-HSD2H6PDH + (Gomez-Sanchez et al., 2008)

Cortical thick ascending limbs (CTAL) MR ++ (Farman et al., 1991)(Bostanjoglo et al., 1998)


GR + (Farman et al., 1991) + (Ackermann et al., 2010)11b-HSD111b-HSD2H6PDH +/� (Tanahashi and Hori, 1980)

Henle’s loop, thin parts of the loop MR + (Farman et al., 1991) + (Uhrenholt et al., 2003)GR + (Farman et al., 1991)11b-HSD111b-HSD2H6PDH + (Gomez-Sanchez et al., 2008)

Interstitial cells, papilla MR + (Farman et al., 1991)GR + (Farman et al., 1991)11b-HSD1 + (Brereton et al., 2001)

+ (Gong et al., 2008)11b-HSD2H6PDH � (Gomez-Sanchez et al., 2008)

Pappilar surface epithelium MR + (Farman et al., 1991)GR + (Farman et al., 1991)11b-HSD111b-HSD2H6PDH + (Gomez-Sanchez et al., 2008)


and it will be important to compare the localization of MR and GRin different cell types during peak glucocorticoids and at nadir dur-ing circadian rhythm. Nevertheless, the authors observed cytoplas-mic localization of both MR and GR in adrenalectomized rats, andlow dose corticosterone replacement led to nuclear translocationof MR but not GR. The GR translocated to the nuclei only in cellsnot expressing 11b-HSD2 (Ackermann et al., 2010). Thus, theobserved differences in nuclear localization of MR and GR likelyreflect their relative affinity for corticosterone. Decreased cortico-sterone levels at high-salt diet may be sufficient for translocationof MR but not GR.

GR was found to be coexpressed with 11b-HSD1 and H6PDHmainly in the third segment of the proximal tubules (Breretonet al., 2001; Gomez-Sanchez et al., 2008; Gong et al., 2008) andprobably plays a role in regulating glucose and lipid uptake andmetabolism. Chronically elevated glucocorticoid activation inproximal tubules is likely to cause adverse metabolic effects anddisturbances in transport processes in these cells and warrantsfurther investigation.

Several investigators reported the expression of MR in glomeru-lar mesangial cells and observed aldosterone-induced cell prolifer-

ation (Greene et al., 1996; Huang et al., 2009; Liu et al., 2010;Mathew et al., 2008; Nishiyama et al., 2005; Terada et al., 2005). Arecent study with cultured rat mesangial cells provided evidencefor the involvement of the MR in the stimulation of mesangial cellproliferation by high glucose medium (Sinclair et al., 2007). Induc-tion of cell proliferation was prevented by incubation with an antag-onist and siRNA against MR and by an inhibitor of extracellularsignal-regulated kinase kinase (MEK). Furthermore, aldosterone-dependent apoptotic and mitogenic effects were demonstrated inhuman mesangial cells (Mathew et al., 2008). The pro-apoptotic ef-fects of aldosterone were prevented by co-treatment with spirono-lactone as well as by antioxidants and free radical scavengers.Aldosterone has been shown to increase reactive oxygen species(ROS) production by a mechanism involving activation of NADPHoxidase in renal and cardiovascular tissues (Egido, 1996; Miyataet al., 2005; Nishikawa et al., 2005; Nishiyama et al., 2004; Satoet al., 2003; Virdis et al., 2002). Long-term administration of aldo-sterone to rats caused mesangial cell proliferation and expansionof the mesangium (Nishiyama et al., 2004). Thus, exposure to chron-ically high aldosterone levels might cause mesangial cell damage,independent of its hemodynamic effects.


Glomerular mesangial cells were initially reported to express11b-HSD1, and an upregulation of its expression was observed inthe presence of the pro-inflammatory cytokines TNF-a and IL-1b(Escher et al., 1997). However, other investigators reported expres-sion of MR, aldosterone synthase (CYP11B2) and 11b-HSD2 in ratmesangial cells, and provided evidence for a role of mitogen-activated protein kinase 1/2, cyclin D1 and cyclin A in the aldoste-rone-induced mesangial cell proliferation and of Smad2- andTGF-b1-dependent stimulation of fibronectin production (Laiet al., 2006; Terada et al., 2005; Zhang et al., 2010). The expressionand role of the respective 11b-HSD enzyme and species differenceshave to be studied.

Recent evidence suggested that elevated CYP11B2 levels andMR activation in podocytes may contribute to the progression ofdiabetic nephropathy (Lee et al., 2009; Nishiyama et al., 2010).Immortalized podocytes expressing MR, CYP11B2 and 11b-HSD2were incubated with physiological (5.6 mM) and high (30 mM)concentrations of glucose (Lee et al., 2009). MR and CYP11B2expression were increased upon high glucose treatment, whereas11b-HSD2 was not altered. Enhanced MR and CYP11B2 expressionwas also found in glomeruli of streptozotocin treated diabeticrats, and aldosterone levels were increased in these animals.Furthermore, treatment of type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats with the MR antagonist eplerenoneenhanced the blood pressure-independent anti-proteinuric effectsof angiotensinogen II type 1 receptor blocker. These observationsindicate that chronically elevated MR activity may contribute toimpaired glomerular function by adverse effects on podocytes.

The bidirectional enzyme 11b-HSD1 has been detected in renalmedullary and interstitial cells that express GR but not MR(Gomez-Sanchez et al., 2008; Rundle et al., 1989). Interestingly,H6PDH seems to be absent in these cells suggesting that anotherenzyme might provide NADPH in the ER or that 11b-HSD1 mightact as a dehydrogenase in these cells to modulate GR activity.The role of 11b-HSD1 in the modulation of GR function in thesecells remains to be clarified.

Thus, there are several cell types in the kidney where the clas-sical view of MR function does not apply. There are open ques-tions such as how MR activity is regulated in glomerular cellsor cells of the macula densa where MR is coexpressed with11b-HSD1 (Bostanjoglo et al., 1998; Gomez-Sanchez et al., 2008;Gong et al., 2008). Moreover, it remains unclear how GR can beregulated by glucocorticoids in renal cortical collecting ducts inthe presence of 11b-HSD2. Saturation of 11b-HSD2 at peak circa-dian and ultradian rhythm would be expected to lead to activa-tion of high affinity MRs rather than lower affinity GRs. Futurestudies have to face the challenge to uncover the mechanismsof MR and GR activation and the consequences in these cells aswell as to elucidate the cross-talk between different renal cells,and between renal cells and cells of the vasculature, adipose tis-sue and immune system.

3. Gastrointestinal tract

The MR plays an important role in the gastrointestinal tract inwater and electrolyte control as well as the regulation of inflam-mation. In the stomach, aldosterone is involved in the regulationof electrolyte transport associated with gastric acid secretion. Spe-cific aldosterone binding sites were detected in the gastric fundicmucosa but not in antral mucosa (Kato et al., 1999). Colocalizationof MR with 11b-HSD2 could be shown on the basis of protein aswell as mRNA in parietal cells of the gastric fundic mucosa. Inthe stomach, the transport of sodium, potassium, chloride, bicar-bonate and protons is mainly mediated by membrane proteins ofparietal cells. The gastric fundic mucosa cells therefore resemble

renal distal tubular epithelial cells as classic mineralocorticoid tar-gets. The relevance of functional MR in the stomach was furtherdemonstrated by the reduced gastric acid secretion after adrenal-ectomy (Kato et al., 1999).

Interestingly, Brereton et al. reported the expression of11b-HSD1 in parietal cells of the stomach using immunohisto-chemistry (Brereton et al., 2001). The expression of 11b-HSD1 instomach was verified by Moore et al. using RNase protection assay(Moore et al., 2000), and H6PDH expression was also reported instomach (Gomez-Sanchez et al., 2008); however, in these studiesthe specific cell types of expression have not been determinedand it needs to be clarified whether 11b-HSD1 has a physiologicalrole in parietal cells.

The distal colon is a well accepted gastrointestinal mineralo-corticoid-responsive tissue (Binder et al., 1986; Rafestin-Oblinet al., 1984; Schulman et al., 1986). Specific binding of radiola-beled aldosterone provided evidence for MR expression in sig-moid, descending and transverse colon as well as epithelialcells of ascending colon, caecum and ileum in humans (Rafes-tin-Oblin et al., 1984). In contrast, Fukushima et al. detectedMR in adult human gut cells using a polyclonal antibody (Fuku-shima et al., 1991). They observed high expression levels in theascending colon but weak staining in the transverse colon andno signals for goblet cells, jejunum and ileum. Hirasawa et al.investigated the expression of MR and 11b-HSD2 in adult and fe-tal tissues (Hirasawa et al., 1997, 1999). They found coexpressionof MR and 11b-HSD2 in the absorptive epithelia of duodenum,jejunum, ileum, colon, and excretory ducts of anal and esopha-geal glands in adult tissues (Hirasawa et al., 1997). High expres-sion of MR and 11b-HSD2 was observed in colonic epitheliumand weak expression in the superficial epithelium of the smallintestine, suggesting relevant MR action in the upper fetal gas-trointestinal tract (Hirasawa et al., 1999). Smith et al. reportedimmunoreactivity for 11b-HSD2 in ileal enterocytes, colonicabsorptive cells and epithelial goblet cells. Lamina propria,Peyer’s patch and goblet cells within the crypts of Lieberkuhndid not stain positive, while the rectum contained both nega-tively and positively staining cells. The expression of 11b-HSD2was further characterized by Naray-Fejes-Toth et al. in a trans-genic mouse strain expressing a Cre recombinase under the con-trol of the endogenous 11b-HSD2 promoter (Naray-Fejes-Tothand Fejes-Toth, 2007). Classical mineralocorticoid target tissuesas well as non-aldosterone-sensitive tissues were evaluated forgalactosidase-mediated staining and results were confirmed bycounterstaining with specific antibodies against 11b-HSD2. TheiCre excision could be detected in colon epithelial cells, cells ofthe external muscular layers and for the jejunum (Naray-Fejes-Toth and Fejes-Toth, 2007).

11b-HSD1 expression has been found in small intestine (Mooreet al., 2000). In addition, 11b-HSD1 expressing macrophage mayplay a role in inflammation of the colon by producing active gluco-corticoids locally at the site of inflammation. In human and rat co-lon samples upregulation of 11b-HSD1 and a concomitantdownregulation of 11b-HSD2 was observed in colitis, indicating arole for local glucocorticoid metabolism in the regulation of colonicinflammation (Zbankova et al., 2007). Future studies shouldaddress the interactions between colon epithelial cells and macro-phage during inflammation.

In conclusion, coexpression of MR and 11b-HSD2 is found indifferent cells of the gastrointestinal tract. The MR is involved inthe regulation of gastric acid secretion in the stomach and in thecontrol of water and electrolyte homeostasis by colon epithelialcells. The role of 11b-HSD1 in parietal cells in the stomach and incells of the small intestine warrants further investigation. Also,the impact of 11b-HSD1-dependent glucocorticoid activation by


infiltrating macrophage during inflammation on MR in colon epi-thelial cells remains to be investigated.

4. Adrenals

The distribution of MR and GR expression within the adrenalgland remains to be investigated. Studies with MR and GR knock-out mice indicated important roles of these receptors for adrenalfunction. In fetal adrenal glands of GR knockout mice, which dieimmediately after birth, an extensive hypertrophy and hyperplasiaof the cortical zones of the adrenal gland was observed with a dis-organized and reduced medullary region and a lack of adrenalinproducing cells (Berger et al., 1996). Hubert et al. studied the im-pact of MR gene disruption on the renin angiotensin aldosteronesystem in 8 days old mice (Hubert et al., 1999). These mice devel-oped pseudohypoaldosteronism type I with high plasma renin,angiotensin II and aldosterone. Histological analyses revealed a sig-nificantly enlarged zona glomerulosa, which extended more deeplytoward the medullary region than in wild-type mice. The zonafasciculata was reduced and hardly detectable in MR knockout ani-mals. Importantly, renin mRNA expression was hardly detectablein wild-type and heterozygous mice but up to ten-fold higher inthe enlarged z. glomerulosa of MR knockout mice. In contrast,angiotensin receptor 1 mRNA was not changed, whereas angioten-sin receptor 2 was 2-fold lower in adrenals of MR knockout mice. Itis not clear whether the observed changes in the adrenal glands areexclusively a result of the systemic effects of the severe sodiumdepletion and hypovolemia and adaptive responses or whetherMR and GR in specific cells of the adrenal gland might contributeto these disturbances.

Using in situ hybridization Shimojo et al. found 11b-HSD1 pre-dominantly in cells at the cortico–medullary junction within theinner cortex, where it was proposed to play a role in regulatingthe supply of cortex-derived corticosterone to the medullary chro-maffin cells (Shimojo et al., 1996). Chromaffin cells, located besidethe z. glomerulosa, are exposed to high concentrations of aldoste-rone and express MR and GR (Brown et al., 1998; Hodel, 2001). Astudy comparing pigs suffering from metabolic syndrome withlean controls, found decreased MR expression in chromaffin cellsof obese pigs with metabolic syndrome (Hu et al., 2009). Chromaf-fin cells isolated from obese but not lean pigs responded to aldoste-rone by an upregulation of the canonical transient receptorpotential channels TRPC1, TRPC5 and TRPC6. This MR-dependenteffect was fully blocked by spironolactone. Interestingly, dexa-methasone upregulated TRPC5 only, but failed to increase mRNAexpression of TRPC1 and TRPC6 (Hu et al., 2009). Further studiesare needed to clarify the role of 11b-HSD enzymes in the differen-tial effects mediated by glucocorticoids and mineralocorticoids andto understand why aldosterone only increased TRPC expression inanimals with metabolic syndrome.

Other investigators applied immunohistochemistry and de-tected 11b-HSD1 in the outer layer of cells corresponding to thez. glomerulosa but not in the z. fasciculata and zona reticularis(Brereton et al., 2001; Gomez-Sanchez et al., 2008). They observedoccasional spots and short streaks radiating through thez. fasciculata and z. reticularis and associated this expression patternto neuronal cells and/or interstitial fibroblasts. Some staining for11b-HSD1 was also observed in the medulla. A relatively highexpression of H6PDH was found in adrenals from rats, with highestexpression in chromaffin cells (Gomez-Sanchez et al., 2008). Thus,H6PDH is not coexpressed with 11b-HSD1 in chromaffin cells, andthe role of NADPH generation in the ER of these cells remains to bedetermined.

11b-HSD2 mRNA was more abundant in the cortex comparedwith medulla and its expression was uniformly distributed over

the adrenal gland (Shimojo et al., 1996). In humans, 11b-HSD2was not detected in adult adrenals but in fetal tissue (Coulteret al., 1999). Similarly, 11b-HSD2 could not be detected in adrenalsfrom adult mice (Cole, 1995; Naray-Fejes-Toth and Fejes-Toth,2007). In contrast, 11b-HSD2 was detected by immunohistochem-istry in the z. fasciculata and reticularis but not in the z. glomerulosaand medulla. 11b-HSD2 staining was observed in cord-like struc-tures, consistent with expression in steroid-secreting cells.

In addition to the classic genomic effects, glucocorticoids werereported to excert non-genomic effects in medullary chromaffincells. Thereby, short term (minutes) treatment with dexametha-sone or cortisol impaired the repetitive stimulation-inducedpotentiation of catecholamine release, which was unaffected bythe use of RU-486 (Park et al., 2008).

Future studies should address the role of 11b-HSDs and theircorresponding receptors on adrenal function. There is limitedknowledge on impaired function of these enzymes in adrenals ininflammation and metabolic diseases.

5. Immune system

Glucocorticoids are potent modulators of the immune systemand most of their effects are mediated either directly or indirectlyby GR (Barnes, 2010; Baschant and Tuckermann, 2010). Gluco-corticoids remain the most abundantly used and potent anti-inflammatory therapeutics. Numerous synthetic steroids areavailable such as dexamethasone, betamethasone, triamcinolone,budenoside and prednisolone. Glucocorticoids are widely used totreat acute inflammation as well as autoimmune driven chronicinflammatory diseases and neuroinflammatory disorders (Hannanet al., 2010; Montano Loza and Czaja, 2007; Tischner and Reichardt,2007). In contrast, much less is known on the role of MR in theregulation of immune function.

Several studies showed that monocytes and macrophages coex-press MR and GR (Harizi et al., 2008; Joyce et al., 1997; Lim et al.,2007; Rickard et al., 2009; Robertson et al., 1993; Usher et al.,2010; Wilson et al., 2009). Interestingly, 11b-HSD1 is absent inthe undifferentiated and cycling monocytes (Thieringer et al.,2001). Once activated and recruited to the inflamed tissue,monocytes undergo differentiation into macrophages. During thisprocess 11b-HSD1 expression is induced and reaches high levelsin the differentiated macrophages. In addition, macrophages showhigh expression of H6DPH. This raises the question how MR and GRin the presence of 11b-HSD1/H6PDH can be regulated distinctlyand how they are involved in the coordination of immuneregulation.

Usher et al. generated mice specifically lacking MR in myeloidcells and showed that MR is essential for efficient macrophageactivation by proinflammatory cytokines (Usher et al., 2010).Macrophage derived from MR-deficient myeloid cells displayedan impaired activation pattern, and in mice deletion of MR in mac-rophages resembled the effects of MR antagonists and protectedagainst cardiac hypertrophy, fibrosis and vascular damage causedby treatment with angiotensin II/L-NAME. Furthermore, myeloid-derived dendritic cells express MR. Herrada et al. demonstratedan aldosterone-mediated increase in CD8+ T-cell activation thatwas dependent on dendritic cells (Herrada et al., 2010).Aldosterone-mediated MR activation induced MAPK signalingand secretion of IL-6 and TGF-b1 by dendritic cells. Further,aldosterone induced Th17 cell-mediated immune response. Thealtered, aldosterone-mediated dendritic cell activity mightpromote inflammatory damage in the heart and other organs(see also section on heart).

MR expression was also found in neutrophils (Bergmann et al.,2010). Incubation of neutrophils with aldosterone inhibited the


activation of NF-jB by interleukin-8 (IL-8) and granulocyte/macro-phage colony-stimulating factor. Spironolactone abolished NF-jBinhibition by aldosterone, indicating an MR-specific effect. Incuba-tion with IL-8 strongly induced TNF-a mRNA expression, an effectthat was prevented by aldosterone. These results suggest anti-inflammatory effects of MR in neutrophils that might be relevantwhen they interact with endothelial cells. Thus, MR seems to medi-ate pro- and anti-inflammatory effects, depending on the cell type.Since immune cells express both MR and GR in the presence of11b-HSD1 it is questionable whether aldosterone acts as the pre-dominant MR agonist in the presence of endogenous glucocorti-coids that are expected to be present at 100–1000 times higherconcentrations. Aldosterone and active glucocorticoids wereshown to exert differential effects on the mitogenesis of immunecell subtypes (Miller et al., 1994). Miller et al. reported an increasedproliferation of neutrophiles in the presence of the GR specific ago-nist RU28368 but significantly lower numbers of neutrophiles inthe presence of aldosterone. Interestingly, corticosterone, despiteits ability to activate both MR and GR, exerted effects indistin-guishable from those seen with the specific GR agonist RU28368.This may be explained by the formation of MR–GR heterodimers,while specific MR effects may be due to aldosterone-activatedMR homodimers.

Not only the type of steroid but also the duration of exposureaffects the mitogenesis of rat splenic lymphocytes (Wiegers et al.,1994), Thereby, short term (minutes) exposure to corticosteroneat a concentration that shows no or very weak activation of GR(3–30 nM), but not the selective GR agonist RU28368, stimulatedproliferation of lymphocytes by a MR-dependent and probablynon-genomic mechanism. On the other hand, long term treatment(hours) with higher glucocorticoid concentrations (0.1–1 lM)showed anti-proliferative effects by a GR-dependent mechanismsince the immunesuppressive effect could be blocked by the GRantagonist RU-486.

6. Brain

Corticosteroids play a pivotal role in the control of brain activityand are involved in regulating stress response, mood, sleepingbehavior, memory function and release of neuroendocrine hor-mones (McEwen et al., 1986). Both MR and GR are expressed inthe brain, with differences in their sites of expression and func-tions. With respect to MR-dependent regulation, the hippocampusrepresents one of the most interesting brain regions. The hippoca-pal regions (dentate gyrus, CA1, CA2, CA3. CA4) were reported toexpress MR and GR (Ahima and Harlan, 1990; Arriza et al., 1988;Cintra et al., 1994; Gomez-Sanchez et al., 2006; Harris et al.,2001; Joels and de Kloet, 1990; Morimoto et al., 1996; Roland etal., 1995; Sheppard and Funder, 1987; van Steensel et al., 1996;Yau et al., 2011) in the absence of 11b-HSD2 (Roland et al.,1995), whereby 11b-HSD1 expression was reported for all hippo-campal regions, with highest levels in the dentate gyrus and theCA1 region (Roland et al., 1995; Sheppard and Funder, 1987; Yauet al., 2011). H6PDH expression was at least demonstrated for neu-rons of the CA2 region (Harris et al., 2001). The observation that11b-HSD1 in neurons catalyzes the regeneration of active gluco-corticoids further indicates its coexpression with H6PDH. A recentanalysis of H6PDH expression revealed a distinct size of the immu-noreactive protein at 60 kDa in whole brain tissue compared with90 kDa for the classical protein (Gomez-Sanchez et al., 2008). It re-mains to be clarified whether an alternatively spliced variant or apost-translationally modified H6PDH is expressed in the brain.

Confocal laser scanning microscopy revealed a specialized nu-clear clustering for MR and GR in neuronal cells of the CA1 region(van Steensel et al., 1996). The two receptors were found in distinct

nuclear domains but also in clusters where they colocalize, indicat-ing the formation of receptor homodimers and heterodimers. Theformation of MR–GR heterodimers in rat hippocampal neuronshas been demonstrated, and activation of GR was shown to inhibitMR-mediated regulation of neuronal function (Joels and de Kloet,1990). Using recombinant receptors Trapp et al. observed en-hanced activation of the MMTV-promoter driven LacZ gene uponcoexpressing MR and GR, compared with cells transfected withone of the receptors only (Trapp et al., 1994). In contrast, Liuet al. coexpressed MR and GR in monkey kidney CV-1 cells andobserved significantly lower activation of a TAT3–TATA-reporterconstruct compared with cells expressing one of the receptors only(Liu et al., 1995). These observations indicate highly cell- andpromoter-specific effects by MR and GR homodimers and heterodi-mers. Nevertheless, on should keep in mind that in such cell-basedexperiments the receptors are overexpressed, whereas theirassociated coactivator and corepressor proteins are present atendogenous levels.

Although the MR in the hippocampus is expected to be predom-inantly occupied and activated by glucocorticoids, aldosterone wasshown to mediate specific effects as demonstrated by Gomez-Sanchez et al. using intracerebroventricular (icv) aldosterone infu-sions at concentrations unable to exert effects after subcutaneousapplication (Gomez-Sanchez, 1986). The reported aldosterone-mediated increase of systemic pressure after icv application waswithout change in urine volume and could be blocked by the spe-cific MR-antagonist prorenone. Moreover, aldosterone actionseems to require normal glucocorticoid tonus since bilateral adre-nalectomy prevented aldosterone-mediated effects (Gomez-Sanchez et al., 1990a,b). Whether aldosterone-specific effects intissues coexpressing 11b-HSD1 and MR are directly regulated byultradian and circardian rhythm of cortisol release remains to beinvestigated. Furthermore, similar to cardiac tissue and skeletalmuscle, the hippocampus represents a non-classic MR tissue,where aldosterone is expected to exert rapid, non-genomic effects(Connell and Davies, 2005; Lastra et al., 2010; Losel and Wehling,2008). The dissection of effects caused by aldosterone and gluco-corticoids remains difficult and requires further investigation.

Importantly, in hippocampal neurons and microglia cells MRand GR are expressed in the absence of 11b-HSD2 (Naray-Fejes-Toth and Fejes-Toth, 2007; Robson et al., 1998) but presence of11b-HSD1 (Pelletier et al., 2007; Rajan et al., 1996; Yau et al.,2001), suggesting predominant occupation of the receptors by11b-hydroxyglucocorticoids. Low levels of glucocorticoids are ex-pected to predominantly act through MR, thereby functioning ina proactive mode by regulating the sensitivity of neuroendocrinestress responses (De Kloet et al., 1998; de Kloet et al., 2000). Highlevels of glucocorticoids, as present during severe stress, lead to theoccupancy of MR and GR, whereby the GR is thought to play a piv-otal role in counteracting MR effects and mediating recovery fromthe stress response.

Excess glucocorticoid action during stress or upon upregulationof 11b-HSD1 by pro-inflammatory cytokines exerts adverse effectson hippocampal neurons and causes impaired cognitive functions.Increased glucocorticoid levels have been associated with cognitiveimpairments and hippocampal atrophy both in rodents and hu-mans (Lupien et al., 1998; Yau et al., 2002). In aging mice, an in-crease in 11b-HSD1 levels in the CA3 hippocampus and parietalcortex correlated with impaired cognitive performance, wherebycirculating glucocorticoid levels and corticosteroid receptorexpression did not correlate with cognitive function (Holmeset al., 2010). Transgenic mice overexpressing 11b-HSD1 specificallyin the forebrain region showed premature age-associated cognitivedeficits, suggesting a causal role of elevated 11b-HSD1 expression.This is supported by the observation that mice deficient in11b-HSD1 have lower intrahippocampal corticosterone levels and


that they show a delayed decline in age-related cognitive function(Yau et al., 2001). A reduced 11b-HSD1 expression in transgenicanimals as well as inhibition of the enzyme resulted in improvedmemory function, suggesting that inhibition of 11b-HSD1 mayshow beneficial effects in treating age-related cognitive disorders(Sooy et al., 2010). A recent study by Yau et al. demonstrated en-hanced 11b-HSD1 activity and mRNA expression in the hippocam-pus of aged mice. The authors provided evidence for beneficialeffects on cognitive function in aged mice upon inhibition of11b-HSD1 (Yau et al., 2011). They showed that aged C57BL/6J micehad impaired spatial memory, which was improved upon adminis-tration of the GR antagonist RU-486. In contrast, the MR antagonistspironolactone had no effect. In aged 11b-HSD1 (�/�) mice spatialmemory became impaired after treatment with spironolactone,whereas RU-486 had no effect. These observations emphasize theimportance of the cross-talk between MR and GR in the regulationof brain function.

In line with the adverse effects of elevated glucocorticoids inthe hippocampus, transgenic expression of 11b-HSD2 in dentategyrus granule cells reversed the adverse effects of high glucocorti-coid treatment on granule cell and CA1 pyramidal cell excitabilityand on spatial reference memory (Dumas et al., 2010).

Inflammation results in increased local and circulating levels ofactive glucocorticoids (for review see (Tischner and Reichardt,2007)). The inflammatory response in the brain involves a coordi-nated action of monocytes, macrophages, astrocytes and microgliacells. Microglia cells express both MR and GR in the presence of11b-HSD1 (Gottfried-Blackmore et al., 2010). Like macrophages,microglia cells belong to the specialized cells of the immune sys-tem. They express MHC II (major histocompatibility complex)and therefore act as professional antigen-presenting cells (APCs)in the brain. Microglia cells are able to produce cytokines and neu-rotrophic factors, thereby modulating the function of astrocytesand neuronal cells. High doses of the synthetic GR-specific gluco-corticoids methylprednisolone and dexamethasone were shownto suppress the expression of MHC II on the surface of microgliacells (Boylan et al., 1999; Kiefer and Kreutzberg, 1991). The sup-pressive effect of these ligands is likely a result of their high con-centrations and GR-selectivity. In contrast, low doses ofendogenous glucocorticoids that mainly act through MR may stim-ulate the inflammatory response.

The regions of the cerebellum (purkinje layer, granular layer,deep nuclei) were demonstrated to coexpress MR and GR (Ahimaand Harlan, 1990; Arriza et al., 1988; Cintra et al., 1994;Gomez-Sanchez et al., 2006; Morimoto et al., 1996). In the neona-tal cerebellum both receptors are coexpressed with 11b-HSD2;however, 11b-HSD2 expression was shown to decline withincreasing age and finally was no longer detectable in the adultcerebellum (Geerling and Loewy, 2006; Robson et al., 1998). Colo-calization of MR and 11b-HSD2 suggests aldosterone sensitivity ofthe receptor. Coexpression of 11b-HSD2 with GR and MR wasfound in the hypothalamus and in several thalamic nuclei (Robsonet al., 1998) such as in the ventromedial nucleus of the hypothal-amus (Naray-Fejes-Toth and Fejes-Toth, 2007; Morimoto et al.,1996; Robson et al., 1998) (Ahima and Harlan, 1990; Cintraet al., 1994; Geerling and Loewy, 2006). Furthermore, MR and11b-HSD2 were both detected by some but not all investigatorsin the locus coerulens, medial vestibular nucleus and paraventric-ular and rhomboid nucleus of the thalamus (Robson et al., 1998)(Harris et al., 2001). Coexpression of MR and 11b-HSD2 in the peri-ventricular regions renders selectivity of MR to aldosterone tomodulate volume regulation and sympathetic outflow as well assalt appetite (Geerling and Loewy, 2006). MR in the absence of11b-HSD2 is found in the anterior hypothalamus and circumven-tricular tissues including chorioid plexus. Coexpression of MRand 11b-HSD2 was also reported for the medulla (nucleus of the

solitary tract, lateral reticular nucleus, external cuneate nucleus,spinal) (Geerling and Loewy, 2006, 2009; Robson et al., 1998).Furthermore, MR and 11b-HSD2 were both detected in the amyg-dala and the subcommissural organ. Moreover, immunohisto-chemistry, in situ hybridization and binding of radiolabeledaldosterone revealed high expression of MR in the lateral septum,medial and central amygdala, olfactory nucleus, layer II of the cor-tex and brain stem sensory and motor neurons (Arriza et al., 1988;De Kloet and Reul, 1987; De Kloet et al., 1998; de Kloet et al., 2000;McEwen et al., 1968). The localization of 11b-HSD2 in these tissueswas confirmed in transgenic mice expressing b-galactosidaseunder the control of the endogenous HSD11B2 promoter(Naray-Fejes-Toth and Fejes-Toth, 2007). In addition to the re-ported tissues such as hippocampus and amygdala, GR expressionwas found in the brain in neurons and glia cells, the ascendingmonoaminergic neurons of the brain stems, the septum as a partof the limbic system and the supraoptic nucleus (Arriza et al.,1988; De Kloet et al., 1998; Naray-Fejes-Toth and Fejes-Toth,2007; Nichols et al., 2005; Tanaka et al., 1997).

In conclusion, the MR has similar affinity for aldosterone andactive 11b-hydroxyglucocorticoids. Therefore, MR function in thebrain strongly depends on the presence or absence of 11b-HSDs,which control ligand availability and regulate the access of aldoste-rone to the receptor. The formation of heterodimers between GRand MR as well as the differential recruitment of coactivatorsand corepressors further increase the level of functional diversityof MR and GR function. The activity of the low-affinity receptorGR is expected to be modulated by glucocorticoid fluctuationsduring circadian and ultradian oscillations of steroid release, whichmay also affect MR function via heterodimerization (Lightmanet al., 2008). Hippocampal neurons, microglia cells and macro-phage express MR and GR in the presence of 11b-HSD1, suggestingan aldosterone insensitive, continuously glucocorticoid occupiedand activated MR. Whether this is indeed the case or whetheraldosterone sensitivity is restored by other mechanisms in vivohas to be further studied. Especially, the distinction betweenglucocorticoid- and aldosterone-mediated effects requires furtherinvestigation.

7. Bone

Maintenance of bone homeostasis critically depends on thefunctional interactions between fibroblasts, osteoblasts and osteo-clasts, and on complex interactions and feed-back regulationinvolving various chemokines, cytokines and hormones. Cortico-steroid receptors and 11b-HSDs play an important role in themodulation of bone homeostasis and offer opportunities for thera-peutic intervention in diseases including osteoporosis and rheuma-toid arthritis. While physiological glucocorticoid concentrationspromote osteoblast differentiation, high concentrations promoteosteoblast apoptosis thereby inhibiting osteoblastogenesis.

Immunohistochemical analysis of human neonatal ribs and iliaccrest biopsy specimens indicated that MR as well as GR and GRbare expressed in neonatal and adult human bone (Beavan et al.,2001). MR and both GR variants were found to be highly expressedin osteoblasts along bone forming surfaces in neonatal rib sections.In contrast, expression was considerably lower in multinucleatedosteoclasts and GR was absent or expressed at very low levels. Sim-ilarly, iliac crest biopsies showed expression of both GR variants inosteoblast-like cells in cancellous surfaces, whereas very fewosteocytes stained positive for GR. MR expression was found inosteoblasts and in about one-third of cancellous osteocytes. Thepresence of mRNA of the two GR variants and of MR was confirmedby RT–PCR in cultured primary human osteoblasts. Evidence forthe lack of GR but presence of GRb expression in human and rat


osteoclasts, and of considerably lower GR and MR in osteoclastscompared with osteoblasts, was supported by other investigators(Abu et al., 2000; Dempster et al., 1997). Interestingly, MR wasnot detected in early fetal bone tissue beyond 12 weeks of gesta-tion (Condon et al., 1998), suggesting a role of this receptor in ter-minal differentiation.

Early observations in patients with apparent mineralocorticoidexcess (AME) provided evidence for a role of 11b-HSD2 in modu-lating bone homeostasis. AME patients suffered, among other com-plications, from retarded growth, osteopenia and minimal traumabone fractures, effects that were ameliorated upon treatment withthe MR antagonist spironolactone (Batista et al., 1986; Milfordet al., 1995). Activation of MR by aldosterone enhanced prolifera-tion of cultured osteoblasts from rat calvaria, an effect inhibitedby specific MR antagonists (Agarwal et al., 1996). Furthermore,MR antagonists inhibited the production of pro-inflammatorycytokines, including TNF-a and INF-c, and have potential in thetreatment of arthritis (Bendtzen et al., 2003).

Using the MG-63 human osteosarcoma cell line, Cooper et al. re-ported a decreased expression of 11b-HSD2 upon treatment withTNF-a or IL-1b (Cooper et al., 2001). In contrast, primary osteo-blasts express 11b-HSD1 and the levels of this enzyme were stim-ulated by exposure to TNF-a or IL-1b, thus leading to enhancedlocal concentrations of active glucocorticoids. The authors pro-posed that pro-inflammatory cytokines may exert some of their ef-fects within bone, e.g. periarticular erosions in inflammatoryarthritis, by increasing local glucocorticoid concentrations.

Jia et al. studied the role of glucocorticoids in transgenic micespecifically expressing 11b-HSD2 in osteoclasts (Jia et al., 2006).Treatment of wild-type and transgenic mice with pharmacologicaldoses of glucocorticoids enhanced apoptosis in cancellous osteo-blasts and decreased osteoblast, osteoid and bone formation.Glucocorticoids stimulated the osteoclast marker, the calcitoninreceptor, on wild-type but not transgenic mice. Importantly, gluco-corticoids decreased the number of cancellous osteoclasts in trans-genic but not wild-type mice. The observed loss of bone density inwild-type mice was prevented by 11b-HSD2 overexpression in thetransgenic line. The authors concluded that the early, rapid loss ofbone caused by glucocorticoid excess resulted from direct actionson osteoclasts.

Glucocorticoids expand the life span of osteoblasts and decreasebone density. An early increased bone resorption followed by adiminished osteoclastogenesis and a consequently decreased boneresorption was observed in a mouse model of glucocorticoid-in-duced osteoporosis (Weinstein et al., 1998). Mice implanted withslow release prednisone pellets displayed early activation of osteo-clastogenesis and adipogenesis as well as prolonged suppression ofosteogenesis (Yao et al., 2008). In this model the synthetic gluco-corticoid receptor ligand prednisone required prior activation by11b-HSD1 in the liver or locally in the osteoblast.

Buttgereit et al. studied the impact of osteoblast-targeted trans-genic overexpression of 11b-HSD2 on joint inflammation, cartilagedamage, and bone metabolism in the K/BxN mouse serum transfermodel of autoimmune arthritis (Buttgereit et al., 2009). Wild-typeand transgenic mice developed acute arthritis but in the latterarthritis and local inflammatory activity were significantly attenu-ated. Transgenic overexpression of 11b-HSD2 ameliorated boneresorption as well as loss of bone volume, and improved osteoblastactivity, suggesting that osteoblasts modulate the immune-medi-ated inflammatory response in a glucocorticoid-dependentmanner.

Intraarticular corticosteroid application in patients withinflammatory arthritis reduced synovial RANKL expression(Makrygiannakis et al., 2006). Glucocorticoids inhibited osteopro-tegerin expression and increased receptor activator of NF-jBligand (RANKL) synthesis by osteoblasts, thereby promoting

osteoclastogenesis (Hofbauer et al., 1999; Makrygiannakis et al.,2006). However, following priming with TNF-a, a condition mim-icking pro-inflammatory milieu of the rheumatoid joint, glucocor-ticoids were found to decrease RANKL expression (Makrygiannakiset al., 2006).

Thus, glucocorticoids affect bone cells differently in the pres-ence or absence of inflammatory mediators and they may have abone conserving effect in rheumatoid arthritis despite of inducingosteoporosis in the spine. Future studies to distinguish betweenMR- and GR-mediated effects are needed.

8. Adipose tissue

Functional adipose tissue consists of preadipocytes and adipo-cytes, and additional cell types such as endothelial cells enablingits high vascularization, fibroblasts, and macrophages responsiblefor the numerous endocrine and immune functions. Adipocytesand adipose tissue infiltrating macrophages are derived from thesame bone marrow stem cell origin, and they express MR and GRin the presence 11b-HSD1 and H6PDH.

There is increasing evidence for a key role of MR in mediatingadverse effects in metabolic disease. Elevated levels of MR werefound in obese, diabetic mice (ob/ob and db/db), which have in-creased expression of pro-inflammatory and pro-fibrotic factorsand reduced expression of adiponectin and PPARc in adipose tissue(Guo et al., 2008; Hirata et al., 2009). Treatment with the MR selec-tive antagonist eplerenone normalized the impaired regulation ofobesity-related genes, suppressed macrophage infiltration andattenuated insulin resistance (Hirata et al., 2009). Moreover, incu-bation of undifferentiated preadipocytes with 10 nM aldosteronefor 24 h increased the expression of TNF-a and MCP1 and de-creased adiponectin and PPARc (Guo et al., 2008). A recent studywith cultured 3T3-L1 and 3T3-F442A adipocytes and human pri-mary preadipocytes reported dose-dependent inhibition of adiposedifferentiation and potent anti-adipogenic effects of the MR antag-onist drospirenone (Caprio et al., 2011). Further evidence for a pro-inflammatory adipogenic effect of MR was provided from a recentstudy with GR- and MR-deficient adipocytes (Hoppmann et al.,2010). Expression of the pro-inflammatory factors IL-6 and MCP1was enhanced in GR knockout adipocytes upon treatment withcorticosterone, indicating an MR-dependent stimulation of thepro-inflammatory factors. Deletion of MR resulted in a completeloss of lipid accumulation, whereas deletion of GR led to rathersubtle disturbances of adipogenesis during early differentiation.These observations are in line with an earlier study using a brownadipocyte cell model (Penfornis et al., 2000). Aldosterone promotedadipocyte differentiation, indicated by an accumulation of intracy-toplasmic lipid droplets and a concentration-dependent increase inintracellular triglyceride content. The aldosterone-dependent ef-fects were not affected by the GR antagonist RU-486 but abolishedby MR antagonists, indicating a key role of MR in the early phase ofadipocyte differentiation.

Glucocorticoids control the terminal differentiation of adiposeprecursor cells and essentially modulate adipocyte function(Gaillard et al., 1991). Given the more than 10-fold higher affinityof MR compared with GR for 11b-hydroxyglucocorticoids, it can beassumed that the MR is occupied by 11b-hydroxyglucocorticoids inpreadipocytes and adipocytes. Depending on the availableglucocorticoid concentration lower affinity GRs are activated andmay counteract the effects of MR through mechanisms that needto be uncovered but likely include receptor heterodimerization.11b-HSD1 is highly expressed in adipose tissue, although itsexpression is considerably lower than in liver. In contrast,11b-HSD2 mRNA and activity was detected only at low levels inadipose stromal vascular cells (Engeli et al., 2004; Lee et al.,


2008). Comparison of the expression of 11b-HSD1 and 11b-HSD2revealed a 22-fold and 8-fold lower expression of the latter insubcutaneous fat, respectively. Moreover, in the obese situationinfiltrated macrophage expressing 11b-HSD1 further increase localcortisol production and MR activation, thus promoting inflamma-tion (Weisberg et al., 2003).

In mouse preadipocytes isolated from mesenteric andsubcutaneous fat, 11b-HSD1 was found to function as oxoreduc-tase, thereby activating glucocorticoids (De Sousa Peixoto et al.,2008). Treatment of mice with high-fat diet, leading to thestimulation of 11b-HSD1 activity, resulted in enhanced preadipo-cyte differentiation in wild-type but not 11b-HSD1 knockoutanimals. It was shown that in the widely used 3T3-L1 fibroblast-like cells 11b-HSD1 expression is absent prior to differentiationbut increases with progression of differentiation and is highlyexpressed in the fully differentiated state (Atanasov et al., 2004;Napolitano et al., 1998). Importantly, H6PDH is similarly expressedbefore and after differentiation (Atanasov et al., 2004). Further-more, a continuous expression of H6PDH was observed duringthe differentiation of human adipose-derived mesenchymal stemcells, indicating that 11b-HSD1 functions as an oxoreductase inboth preadipocytes and adipocytes (Senesi et al., 2008). H6PDHknockout mice, where 11b-HSD1 is thought to act as a dehydroge-nase, display diminished lipogenesis, lipolysis rates and fatty acidrelease upon fasting, and they have significantly reduced adiposetissue mass, although average adipocyte size was not altered(Bujalska et al., 2008).

The association of enhanced local glucocorticoid activation by11b-HSD1 with visceral obesity and the development of insulinresistance, type 2 diabetes and cardiovascular disease is beingextensively studied (reviewed in (Gathercole and Stewart, 2010;Staab and Maser, 2010)). Based on the fact that the MR has morethan 10-fold higher affinity for cortisol than GR and that it is coex-pressed with 11b-HSD1 and H6PDH in preadipocytes and adipo-cytes, we propose that the pro-inflammatory and pro-adipogeniceffects of elevated local glucocorticoid concentrations are mainlymediated by activation of MR. Thus, a combination of an MR antag-onist and an 11b-HSD1 inhibitor may prove beneficial in the treat-ment of metabolic disease.

9. Heart

In the heart, MR expression has been demonstrated in cardio-myocytes, cells of atria and ventricles, the aorta and pulmonaryartery as well as in vascular endothelial and smooth muscle cells(Funder et al., 1989; Jaffe and Mendelsohn, 2005; Jaffe et al., 2007;Lombes et al., 1992) (Table 2). In addition, macrophages, which infil-trate the heart during inflammation, express high levels of MR.

Several clinical studies revealed an association of elevated MRactivity with vascular inflammation and cardiac fibrosis, and an in-creased risk for congestive heart failure. Supplementation of thestandard therapy of angiotensin-converting enzyme inhibitor, loopdiuretic and digoxin for patients with heart failure, with the MRantagonists spironolactone (RALES (Pitt et al., 1999)) or eplerenone(EPHESUS (Pitt et al., 2003b)) demonstrated a 30% and 15%improvement in mortality respectively. Furthermore, treatmentwith MR antagonists decreased blood pressure in patients withessential hypertension and left ventricular hypertrophy (4E-leftventricular hypertrophy study (Pitt et al., 2003a)). The MR-depen-dent exacerbation of tissue damage in cardiac ischemia can beameliorated by eplerenone (Fraccarollo et al., 2008). Thus, MRantagonists have a beneficial impact on post-myocardial infarctiontherapy and in treatment of patients with essential hypertension.

In line with clinical trials, animal studies addressed the mecha-nisms of MR activation in heart disease and provided evidence for

beneficial effects of antagonists (Brown, 2008; Robert et al., 1994;Rocha et al., 2000, 2002a,b; Turchin et al., 2006; Young et al., 1994,1995). A causal role for MR was demonstrated in transgenic miceby conditional overexpression specifically in cardiomyocytes(Ouvrard-Pascaud et al., 2005). Overexpression of MR resulted inion channel remodeling with prolonged ventricular repolarization,severe ventricular arrhythmias and increased mortality.

MR expression in cardiac derived fibroblasts has also been re-ported; however, contradictive observations warrant further con-firmatory studies. Regardless of mRNA expression, the function ofthe MR multi-protein complex in cardiac fibroblasts, if existent,might differ from that in cardiomyocytes (Lother et al., 2011). Inmice, chronic severe pressure overload due to aortic constrictioncaused cardiac hypertrophy, followed by left ventricular dilatationand heart failure (Lother et al., 2011). Cardiomyocyte-specific dele-tion of MR prevented the increase in left ventricular inner diastolicdiameter and wall tension but did not prevent cardiac hypertro-phy. Similarly, eplerenone did not prevent cardiac hypertrophybut delayed the transition to myocardial failure (Kuster et al.,2005; Lother et al., 2011). Cardiac fibrosis caused by chronic pres-sure overload was not reduced in mice with a specific knockout ofMR in fibroblasts (Lother et al., 2011). The use of MR specific siRNAin fetal human cardiac fibroblasts suggested an MR-independentincrease of elastine production after treatment with aldosterone(Bunda et al., 2009). Thereby, non-genomic effects, which are inde-pendent of MR expression, might provide an explanation for con-tradictive observations.

Deletion of MR in macrophages attenuated the production ofROS in the heart and prevented inflammation and fibrosis inducedby treatment with deoxycorticosterone/salt (Rickard et al., 2009)or angiotensin II (Usher et al., 2010). These observations indicatea key role of MR in infiltrating macrophages in the progression ofvascular inflammation and cardiac fibrosis.

While no or very low expression of 11b-HSD1 and 11b-HSD2was reported for human cardiomyocytes (Brereton et al., 2001),11b-HSD2 expression was demonstrated for both human endothe-lial cells and vascular smooth muscle cells (Jaffe et al., 2007; Kayes-Wandover and White, 2000; Smith et al., 1996). In contrast to thehuman situation, 11b-HSD1 expression was found in rodent car-diac vascular smooth muscle cells, whereby the enzyme activitywas higher in quiescent cells compared with proliferating cells(Brem et al., 1995). Although some discrepancies may be due tocontamination of vascular smooth muscle cell preparations withendothelial cells, species-specific differences need to be consideredand care should be taken in extrapolating results from studies withrodents to the human situation.

11b-HSD2 expression is low in fetal mouse heart, whereas MR ishighly expressed. Evidence for an important role of 11b-HSD2 inthe heart was provided by observations in 11b-HSD2 knockoutmice, which exhibit significantly enlarged heart size and a highmortality rate (Qin et al., 2003). Reini et al. reported a highly signif-icant negative correlation between 11b-HSD2 expression and thethickness of the left ventricular wall in sheep (Reini et al., 2006).The chronic administration of moderate doses of cortisol duringlate gestation resulted in significantly decreased 11b-HSD2 expres-sion in the heart and caused an increase of the fetal heart weight.

Since 11b-HSD2 converts active into inactive glucocorticoids, itrestores aldosterone specificity of MR and inhibits GR activation.Thus, both GR and MR might be responsible for the developmentof elevated heart size. Interestingly, transgenic mice with a car-diac-specific overexpression of 11b-HSD2 developed cardiachypertrophy, which was attenuated after treatment with eplere-none (Qin et al., 2003). In the presence of high 11b-HSD2 activity,circulating glucocorticoids may no longer be sufficiently high toactivate GR in order to counteract aldosterone-dependent MRactivity. In contrast, a lack of 11b-HSD2 activity is expected to

Table 2Expression of mRNA and protein of MR, GR, 11b-HSD2, 11b-HSD1 and H6PDH in cells of the heart.

HEART Protein RNA

Whole heart MR + (Gomez-Sanchez et al., 2006 ;Lopez-Andres et al., 2008 #5348}

+ (Arriza et al., 1987)+ (Yoshida et al., 2005)+ (Lopez-Andres et al., 2008)

GR + (Arriza et al., 1987)+ (Lopez-Andres et al., 2008)

11b-HSD1 + (Albiston et al., 1995)+ (Gomez-Sanchez et al., 2008)+ (Brereton et al., 2001)

11b-HSD2 ++ (Lombes et al., 1995)+ (Walker et al., 1991)

H6PDH (+) (Gomez-Sanchez et al., 2008) + (Gomez-Sanchez et al., 2008)

Endocardial intestinal cells/Cellssurrounding cardiac vessels

MRGR11b-HSD1 (+) (Brereton et al., 2001)11b-HSD2H6PDH

VSMC MR + (Lombes et al., 1992)+ (Gomez-Sanchez et al., 2006;Lopez-Andres et al., 2008)

GR11b-HSD1 ++ (Brereton et al., 2001)

++ (Hadoke et al., 2001)11b-HSD2H6PDH

Cardiomyocytes MR + (Lombes et al., 1995)+ (Lombes et al., 1992)+ (Lopez-Andres et al., 2008)

+ (Lombes et al., 1995)+ (Arriza et al., 1987)+ (Le Menuet et al., 2010)++ (Klusonova et al., 2009)++ (Lopez-Andres et al., 2008)

GR + (Lopez-Andres et al., 2008) + (Klusonova et al., 2009)+ (Lopez-Andres et al., 2008)

11b-HSD1 � (Brereton et al., 2001)11b-HSD2H6PDH

Endothelial cells MR + (Lombes et al., 1992)GR11b-HSD111b-HSD2 + (Christy et al., 2003)

� (Walker et al., 1991)H6PDH

Aorta MR + (Lombes et al., 1992) + (Christy et al., 2003)+ (Uhrenholt et al., 2003)

GR + (Christy et al., 2003)+ (Uhrenholt et al., 2003)

11b-HSD1 + (Gomez-Sanchez et al., 2008) + (Hadoke et al., 2001)+ (Christy et al., 2003)

11b-HSD2 + (Walker et al., 1991) + (Hadoke et al., 2001)+ (Uhrenholt et al., 2003)+ (Walker et al., 1991)+ (Christy et al., 2003)

H6PDH + (Gomez-Sanchez et al., 2008) + (Gomez-Sanchez et al., 2008)

Aorta VSMC MR + (Lombes et al., 1992)+ (Caprio et al., 2008)

+ (Caprio et al., 2008; Tsugita et al., 2008)+ (Tsugita et al., 2008)

GR + (Tsugita et al., 2008)11b-HSD1 + (Christy et al., 2003)

+ (Tsugita et al., 2008)11b-HSD2 + (Caprio et al., 2008)

+ (Walker et al., 1991)+ (Caprio et al., 2008; Tsugita et al., 2008)+ (Walker et al., 1991)

H6PDH

Aorta endothelial cells MR + (Lombes et al., 1992)+ (Caprio et al., 2008)

++ (Caprio et al., 2008)

GR11b-HSD1 + (Brem et al., 1998)11b-HSD2 + (Caprio et al., 2008) + (Christy et al., 2003)

+ (Caprio et al., 2008)+ (Brem et al., 1998)

H6PDH

Mesenteric artery/caudal artery MRGR11b-HSD111b-HSD2 ++ (Walker et al., 1991) + (Takeda, 2003)H6PDH

(continued on next page)


Table 2 (continued)

HEART Protein RNA

Atria MR ++ (Lombes et al., 1992)GR11b-HSD111b-HSD2 (+) (Naray-Fejes-Toth and Fejes-Toth, 2007)H6PDH

Ventriculum MR + (Rossier et al., 2010)GR + (Rossier et al., 2010)11b-HSD1 ++ (Rossier et al., 2010)11b-HSD2 (+) (Naray-Fejes-Toth and Fejes-Toth, 2007) + (Rossier et al., 2010)H6PDH

Left ventriculum MR + (Yoshida et al., 2005)+ (Lombes et al., 1995)+ (Lombes et al., 1992)

+ (Uhrenholt et al., 2003)+ (Yoshida et al., 2005)+ (Lombes et al., 1995)

GR + (Uhrenholt et al., 2003)11b-HSD1 ++ (Klusonova et al., 2009)11b-HSD2 ++ (Klusonova et al., 2009) + (Klusonova et al., 2009)H6PDH + (Klusonova et al., 2009; Uhrenholt et al., 2003)

Right ventriculum MR + (Lombes et al., 1995) + (Lombes et al., 1995)GR11b-HSD1 ++ (Klusonova et al., 2009)11b-HSD2 ++ (Klusonova et al., 2009) + (Klusonova et al., 2009)H6PDH + (Klusonova et al., 2009)

Small intraventricular vessels MR � (Lombes et al., 1995)GR11b-HSD111b-HSD2H6PDH


cause glucocorticoid-dependent MR activation and GR might nolonger be able to efficiently counteract the fully activated MR, thusproviding an explanation why both a lack of 11b-HSD2 and itsoverexpression cause cardiac hypertrophy.

10. Skeletal muscle

Skeletal muscles have a high demand of energy, and glucocorti-coids are essentially regulating insulin-stimulated glucose uptake,glycogen storage and carbohydrate metabolism. Chronically ele-vated glucocorticoid levels have been associated with insulin resis-tance and impaired carbohydrate metabolism as well as catabolicpathways causing muscle atrophy. Recent studies provided evi-dence for a functional expression of MR, besides GR, in soleus mus-cle (Burniston et al., 2005). High aldosterone levels, in addition totheir cardiotoxic effects, led to the induction of apoptosis in soleusmuscle. In soleus muscle, high aldosterone levels increased NADPHoxidase and ROS production decreased Akt phosphorylation andGLUT4 expression, and induced insulin resistance (Lastra et al.,2008). Spironolactone ameliorated aldosterone-induced cardiacand skeletal muscle myopathy, providing evidence for an MR-dependent mechanism. As in cardiomyocytes, 11b-HSD2expression could not be detected using immunofluorescence andribonuclease protection assays in skeletal muscle of normal andCre-recombinant male mice (Moore et al., 2000; Naray-Fejes-Tothand Fejes-Toth, 2007).

11b-HSD1 is expressed in skeletal muscle with a 13-times high-er level in soleus (type I-rich fibers) compared with tibialis anterior(type IIb-rich fibers) (Semjonous et al., 2011). Impaired regulationof 11b-HSD1 activity in myotubes from diabetic patients may con-tribute to insulin resistance (Jang et al., 2007; Morgan et al., 2009;Whorwood et al., 2002). H6PDH is also expressed in soleus and tib-ialis anterior and plays an important role in the regulation of mus-cle cell differentiation and function (Semjonous et al., 2011). It canbe assumed that chronic hyperglycemia leads to enhanced local

glucocorticoid activation by 11b-HSD1/H6PDH, thereby activatinglocal GR and/or MR and contributing to impaired glucose transportand insulin resistance. The role of H6PDH has been studied intransgenic mice. H6PDH deficient mice developed a vacuolatingmyopathy, predominantly manifested in type II muscle fibers(Lavery et al., 2008). In further studies with H6PDH/11b-HSD1double knock-out mice, this phenotype was clearly associated withH6PDH deficiency, independent of 11b-HSD1 function (Semjonouset al., 2011).

Fiber type differentiation can be influenced by physical activity.Marathon runners, for example, show a type I-rich fiber composi-tion of the gastrocnemius, whereas a type IIb-rich composition isobserved in sprinters. Thus, fiber type differentiation may bemodulated by the level of energy demand and redox reactions inthe endoplasmic reticulum. Whether and how glucocorticoids areinvolved in these processes remains unclear.

The lack of 11b-HSD1 oxoreductase activity in knockout micemay be compensated by an activation of the HPA axis leading tohigher circulating corticosterone levels (Harris et al., 2001),although strain-dependent differences need to be considered(Carter et al., 2009). Contradictory findings were reported concern-ing serum corticosterone concentrations in H6PDH-deficient mice.Significantly increased adrenal weight and elevated plasmacorticosterone concentrations were reported by two independentgroups (Lavery et al., 2007; Rogoff et al., 2007); however, two otherstudies reported significantly decreased plasma corticosteronelevels in H6PDH-deficient animals (Lavery et al., 2006; Semjonouset al., 2011). Since all of these reports are based on data from trans-genic mice of the same background, i.e. C57BL6J strain, the reasonfor the observed differences remains unclear but may include tech-nical limitations in the quantification of glucocorticoids. Neverthe-less, 11b-HSD1 was significantly upregulated in H6PDH knockoutmice in tibialis anterior, but not in soleus ^muscle or in the liver(Semjonous et al., 2011).

The skeletal muscle is a classic insulin-sensitive tissue. Over-activation of MR is likely to result in increased oxidative stress,


thereby favoring the development of insulin resistance. Western-style diet (high contents of salt, saturated fat and fructose butlow contents of polyunsaturated fat and fibers) has been associatedwith a nutrition-mediated stimulation of the RAAS and enhancedNADPH-oxidase activity and ROS production, which is likely topromote inflammation (Lastra et al., 2010). Inflammation is fol-lowed by enhanced infiltration of macrophages, which may leadto locally increased glucocorticoid concentrations that further in-crease MR activation in skeletal muscle. Furthermore, aldosteroneand cortisol (corticosterone in rodents) both induce muscle atro-phy. Since spironolactone ameliorated myopathy, the action ofaldosterone is likely mediated by the classic genomic pathway. Arecent publication reported a direct relation between 11b-HSD1expression and activity and the expression of two accepted muscleatrophy marker proteins, the E3-protein ligases atrogin-1 andMuRF-1 (Biedasek et al., 2011). Whether aldosterone acts throughsimilar pathways has to be investigated. However, non-genomiceffects of aldosterone, not mimicked by cortisol, have been re-ported for tissues coexpressing 11b-HSD1 and MR, i.e. in skeletalmuscle (Christ et al., 2001; Lastra-Lastra et al., 2009).

The role of MR in skeletal muscle is not fully understood. Stud-ies distinguishing between effects requiring transcriptional activityof MR and rapid non-genomic MR-dependent and -independent ef-fects of corticosteroids are needed.

11. Skin

Glucocorticoids are widely used in the treatment of inflamma-tory and hyperproliferative skin disorders. A major limitation,however, is the development of skin atrophy (Schacke et al.,2002). The relative contribution of GR and MR to skin atrophy re-mains unclear. In situ hybridization and immunohistochemistryrevealed MR expression in human keratinocytes of the epidermis,in sweat glands and sebaceous glands, and in hair follicles(Kenouch et al., 1994; Zennaro et al., 1997). Mice overexpressingMR specifically in keratinocytes and hair follicles exhibited devel-opmental and post-natal impairments of the epidermis and hairfollicles (Sainte Marie et al., 2007). Transgenic mice showedpremature epidermal barrier formation at embryonic day 16.5,decreased hair follicle density and epidermal atrophy, andincreased keratinocyte apoptosis at embryonic day 18.5, andpremature eye opening when MR was overexpressed throughoutgestation. When MR expression was induced after birth, micedeveloped alopecia and hair follicle cysts.

Important information on the role of GR in skin was providedfrom transgenic mice overexpressing GR specifically in keratino-cytes (Perez et al., 2001). Newborn mice exhibited severe skinlesions due to epidermal hypoplasia and underdeveloped dysplas-tic hair follicles. In adult mice, an impaired hyperplastic andinflammatory response to the tumor promoting agent TPA withimpaired NF-jB signaling was observed.

11b-HSD2 activity was found in isolated sweat glands but wasvery low or absent in epidermis biopsies (Kenouch et al., 1994).Whereas MR was detected in excretory ducts in the basal celllayers, 11b-HSD2 was found in the luminal cells of the ducts(Hirasawa et al., 1997). 11b-HSD2 was also absent in sebaceousand apocrine glands, but mRNA expression and immunoreactivitywas detected in the highly vascularized dermis in arterioles (Smithet al., 1996).

The therapeutic efficacy of dermal applications of cortisone andprednisone is dependent on 11b-HSD1 oxoreductase activity,which was found to be higher in mouse compared with humanskin biopsies (Tiganescu et al., 2011). H6PDH was found to behighly expressed in whole human skin specimens, although nospecific localization was determined. Expression of 11b-HSD1 in

mouse skin was demonstrated by several groups using RT–PCR,immunodetection as well as transgenic animals (Moore et al.,2000; Naray-Fejes-Toth and Fejes-Toth, 2007; Tiganescu et al.,2011). Tiganescu et al. localized 11b-HSD1 expression in mice tokeratinocytes in the epidermis, and to dermal standing fibroblastsand hair follicles (Tiganescu et al., 2011). In humans, 11b-HSD1expression was shown to be sex-hormone dependent. Pre-meno-pausal women express higher 11b-HSD1 levels in epidermalkeratinocytes than post-menopausal women. The opposite wasfound in the dermis, where 11b-HSD1 expression was higher inpost-menopausal compared with pre-menopausal women.

In a recent study, aldosterone was found to modulate the depo-sition of extracellular matrix in human skin (Mitts et al., 2010).Aldosterone stimulated the expression of collagen type I and elas-tin, and enhanced elastic fiber deposition in primary cultured skinfibroblasts. Interestingly, spironolactone and eplerenone stimu-lated the elastogenic effect of aldosterone. The authors providedevidence for a MR-independent mechanism involving the activa-tion of insulin growth factor-I receptor and suggested the use ofaldosterone in therapy for dermal lesions to prevent their recur-rence after surgical excision. Although the underlying mechanismfor these observations needs to be elucidated, these observationsindicated that not all effects of aldosterone are mediated by MR.

The skin, like skeletal and cardiac muscle and some regions ofthe brain, belongs to the tissues expressing MR in the presenceof 11b-HSD1 where glucocorticoids are thought to act as predom-inant MR ligands. In addition, it was reported that rat skin ex-presses steroidogenic activity (Slominski et al., 2000). Therelevance of local steroid production for MR- and GR-mediatedregulation of gene expression remains to be elucidated. Neverthe-less, aldosterone was demonstrated to increase KATP channel activ-ity by a rapid and non-genomic mechanism in frog skin (Urbachet al., 1996), and it will be important to further study non-genomicaldosterone- and cortisol-mediated effects in human skin.

12. Outlook

The analysis of expression patterns of MR, GR, 11b-HSD2, and11b-HSD1/H6PDH in various organs and cell types contributed sig-nificantly to the current understanding of MR function. However,there are several key questions that need to be addressed in futurestudies, including the mechanism of MR activation in cells coex-pressing 11b-HSD1/H6PDH. Varying ligand availability, regulatedby circadian rhythm and hourly ultradian oscillations, modulatesMR and GR function in different cells of a tissue. Especially in cellscoexpressing both receptors, ligand availability seems to deter-mine the transcriptional activity of the MR (Sarabdjitsingh et al.,2010). Artificial disturbance of the ultradian rhythm in humansand rats revealed that brain GR protein levels and translocation fol-low an ultraradian triggered phasic response, whereas MR remainsunaffected (Lightman et al., 2008; Sarabdjitsingh et al., 2010). Thisnon-genomic, proteasome-dependent process likely affects hetero-dimerization of MR and GR, suggesting that corticosteroid effectsare highly time-dependent.

The functional interaction of MR and GR and modulation oftheir activities by receptor-specific associated proteins as well aspost-translational modifications of receptors and associatedproteins have to be further investigated. Alternative MR ligandsand ligand-independent activation of MR might be relevant insome situations where it is likely to depend on cell-specific regula-tion. In the last two decades, steroid-induced non-genomic effectswere reported for various tissues such as vascular smooth musclecells (VSMCs) (Christ et al., 1995; Wehling et al., 1995), humanmononuclear leukocytes (Wehling et al., 1991) and cardiac tissue(Mihailidou et al., 2004). In VSMCs, aldosterone-induced non-


genomic effects were observed to occur within seconds to minutes.They were unaffected by the classic MR antagonist spironolactoneand not mimicked by the glucocorticoid cortisol (Wehling et al.,1995). Nevertheless, subsequent studies revealed that aldoste-rone-specificity of these rapid effects in VSMCs was mediated by11b-HSD2 that prevented MR activation by glucocorticoids.Moreover, these rapid aldosterone effects could be blocked bythe open E-ring, water soluble MR antagonist RU28318 (Alzamoraet al., 2000). Non-genomic effects increase the complexity of MRfunction, and in some but not all cases they are dependent on11b-HSD enzymes. Whether non-genomic effects are mediatedvia classic MR, distinct membrane-associated aldosterone sensitivereceptors or both has to be determined (Losel and Wehling, 2008).At least in some cases classical receptors can be excluded as clearlydemonstrated by the use of MR-knockout mice (Haseroth et al.,1999).

In order to understand the mechanisms underlying the adverseeffects of impaired corticosteroid regulation, future research has toelucidate the cell-specific differences in MR and GR regulation aswell as their control by 11b-HSDs. Further, it will be importantto distinguish between genomic and non-genomic MR-dependentand -independent effects of corticosteroids and to elucidate time-dependent modulation of receptor activation and inactivation.

Disclosure statement

The authors of this manuscript have nothing to declare.

Acknowledgements

This work was supported by the Swiss National Science Founda-tion (No. 31003A-124912). A.O. has a Chair in Molecular andSystems Toxicology from the Novartis Research Foundation.

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