1. Top of page
  2. Abstract
  3. Activation of MR by Cortisol
  4. Biology of 11β-HSD2
  5. Bile Acids Inhibit 11β-HSD2
  6. Other Mechanisms Reducing 11β-HSD2 Activity: Nitric Oxide, Angiotensin II, Shear Stress, Hypoxemia, and TNF-α
  7. Therapeutic Implications
  8. References

Exaggerated renal sodium retention with concomitant potassium loss is a hallmark of cirrhosis and contributes to the accumulation of fluid as ascites, pleural effusion, or edema. This apparent mineralocorticoid effect is only partially explained by increased aldosterone concentrations. I present evidence supporting the hypothesis that cortisol confers mineralocorticoid action in cirrhosis. The underlying molecular pathology for this mineralocorticoid receptor (MR) activation by cortisol is a reduced activity of the 11β-hydroxysteroid dehydrogenase type 2, an enzyme protecting the MR from promiscuous activation by cortisol in healthy mammalians. (HEPATOLOGY 2006;44:795–801.)

Renal sodium retention and potassium loss are observed in many patients suffering from cirrhosis. Traditionally, this abnormality is attributed to secondary hyperaldosteronism as a consequence of renal hypoperfusion related to intra-abdominal fluid sequestration.1 This concept has been questioned for 2 reasons. First, patients with cirrhosis accumulating ascites can show renal sodium retention in the presence of normal plasma aldosterone concentration and increased circulating concentrations of natriuretic peptides2–8 and second, renal sodium retention precedes intra-abdominal fluid sequestration in some situations, and therefore a secondary hyperaldosteronism does not explain the abnormal renal handling of sodium and potassium.2–4 Many of these patients have a normal renal plasma flow and glomerular filtration rate. Therefore, sodium retention cannot be explained on the basis of an impaired renal perfusion or a decreased filtered sodium load7 and an unknown mechanism might induce sodium retention.9 Because this type of renal sodium avidity is linked with enhanced renal potassium loss and blocked by aldosterone antagonists, one is tempted to speculate that the underlying mechanism is an activation of mineralocorticoid receptor (MR). Several independent groups of investigators demonstrated that for a given renal sodium excretion the values for aldosterone were too low in patients with cirrhosis and therefore hypothesized that these findings are explained by an increased renal tubular sensitivity to aldosterone.10–12 Here, the evidence is given for another hypothetical mechanism, which might mimic the presumed increased renal tubular sensitivity to aldosterone, i.e., the presence of a MR-activating ligand other than aldosterone. This ligand is most likely cortisol. MR activation by cortisol is not explained by an enhanced adrenal production rate and/or increased serum concentrations of cortisol in these patients, but by a reduced activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which allows promiscuous activation of MR by the glucocorticoid cortisol.

Activation of MR by Cortisol

  1. Top of page
  2. Abstract
  3. Activation of MR by Cortisol
  4. Biology of 11β-HSD2
  5. Bile Acids Inhibit 11β-HSD2
  6. Other Mechanisms Reducing 11β-HSD2 Activity: Nitric Oxide, Angiotensin II, Shear Stress, Hypoxemia, and TNF-α
  7. Therapeutic Implications
  8. References

Initially identified in the classic mineralocorticoid-responsive tissues including the aldosterone-sensitive part of the distal nephron, colon, or salivary glands, MR acts as a ligand-inducible transcription factor.13, 14 The corticosteroid aldosterone was considered to be the physiological endogenous mineralocorticoid ligand of MR because it has a high affinity for MR, but a lower affinity for glucocorticoid receptor (GR). Conversely, cortisol (in humans) and corticosterone (in rodents) have a high affinity for GR and were therefore considered to be the endogenous glucocorticoids. These 2 glucocorticoids, however, have the same affinity for MR as aldosterone and are present in higher concentrations by several orders of magnitude. Nevertheless, aldosterone appeared to account for the main mineralocorticoid effects in vivo. In 1988, two independent groups proposed that the specificity of aldosterone for MR in vivo is given by a prereceptor mechanism, which allows inactivation of the 11β-hydroxyglucocorticoids cortisol and corticosterone, but not aldosterone because it is mainly present as a C11-C18 hemi-ketal in the physiological milieu (Fig. 1).15, 16 This prereceptor mechanism is abrogated in the rare patients with a loss of function mutation in the 11β-HSD2, a disease state named apparent mineralocorticoid excess (AME) and characterized by hypokalemic hypertension with low renin and aldosterone levels.17, 18 AME is mimicked by ingestion of licorice in healthy subjects19 and is the proof of principle that a low activity of 11β-HSD2 induces an enhanced renal potassium excretion relative to renal sodium excretion. As a corollary, disease states with an increased renal sodium avidity and low serum potassium concentrations in the absence of high aldosterone levels are candidate entities for a reduced activity of 11β-HSD2. The biology of 11β-HSD2 has to be summarized before analyzing whether a reduced activity of 11β-HSD2 is relevant in patients with cirrhosis, an entity with an enhanced renal potassium excretion and renal sodium avidity.

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Figure 1. The intracellular concentrations of steroid molecules available for binding to GR or MR depend on the free extracellular concentrations available for diffusion into the cytoplasm and the intracellular prereceptor control mechanism constituted by the 11β-hydroxysteroid dehydrogenase type 1 and 2 (11β-HSD1, 11β-HSD2) enzymes. Whereas 11β-HSD1 acts predominantly as a reductase and converts the 11-keto-steroid cortisone with virtually no affinity for MR and GR into the 11β-hydroxyglucocorticoid cortisol with a high affinity for both GR29, 58 and MR, 11β-HSD220 is exclusively an oxidase and inactivates cortisol into cortisone, which allows protection of MR-expressing cells from promiscuous activation of MR by the glucocorticoid hormone cortisol. GRE, glucocorticoid-response element; MRE, mineralocorticoid-response element (from Frey et al.68).

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Biology of 11β-HSD2

  1. Top of page
  2. Abstract
  3. Activation of MR by Cortisol
  4. Biology of 11β-HSD2
  5. Bile Acids Inhibit 11β-HSD2
  6. Other Mechanisms Reducing 11β-HSD2 Activity: Nitric Oxide, Angiotensin II, Shear Stress, Hypoxemia, and TNF-α
  7. Therapeutic Implications
  8. References

The 11β-HSD2 converts biologically active 11β-hydroxyglucocorticoids into inactive 11-keto-steroids20 (Fig. 1). This enzyme has a nanomolar Km for glucocorticoids, utilizes NAD+ preferentially as a cofactor, and is located in the endoplasmic reticulum membrane with a cytoplasmic orientation of its catalytic domain.20, 21 The 11β-HSD2 exhibits a distinct tissue-specific constitutive expression in classical mineralocorticoid target tissues, such as epithelial cells from colon and renal collecting tubules. The rigorous tissue-specific control of expression of 11β-HSD2 has been elucidated in part by in vivo footprinting22 and appears to be explained by an epigenetic mechanism, DNA methylation.23 Two different signal transduction pathways are involved in the regulation of 11β-HSD2, activation of protein kinase C (PKC) and mitogen-activated protein kinases (MAPKs) or the activation of MAPKs by a PKC-independent pathway.24–26

Bile Acids Inhibit 11β-HSD2

  1. Top of page
  2. Abstract
  3. Activation of MR by Cortisol
  4. Biology of 11β-HSD2
  5. Bile Acids Inhibit 11β-HSD2
  6. Other Mechanisms Reducing 11β-HSD2 Activity: Nitric Oxide, Angiotensin II, Shear Stress, Hypoxemia, and TNF-α
  7. Therapeutic Implications
  8. References

In the early 1990s, the Hierholzer group observed that bile inhibits the interconvertion of 11β-hydroxy- and 11-ketosteroids in a mixture of microsomal enzymes.27, 28 After the 11β-HSD1 and 11β-HSD2 enzymes had been cloned20, 29 the inhibitory potential of human bile and 10 individual bile salts on the specific activity of 11β-HSD1 and 11β-HSD2 was assessed in COS-1 cells transfected with the corresponding plasmids.30 Various bile acids inhibited the oxidative activity of 11β-HSD2 dose-dependently in concentrations considered to be relevant in humans with cholestasis.30 A further analysis of urinary bile acids from 12 patients with biliary obstruction by gas chromatography/mass spectrometry established that the concentration-dependent effect of bile acids on the 11β-HSD2 was relevant when assessed in cell lysates.31 It appeared that the concentrations required to inhibit the enzyme by 50% (IC50 values) were between 7 and 38 μmol/L for lithocholic, chenodeoxycholic (CDCA), and deoxycholic acid (DCA).31 Probably more informative were the analyses of MR-translocation and MR-transactivation studies in whole cells.31, 32 In the absence of cortisol, CDCA and DCA, but no other bile acid, mediated nuclear translocation of tagged MR from the cytoplasm into the nucleus in HEK-293 cells, but no transactivation of the cotransfected reporter plasmid MMTV-lacZ (mouse mammary tumor virus), which contains steroid-responsive elements. Thus, some bile acids can bind to the MR and induce a translocation of MR from the cytoplasm to the nucleus without deploying a mineralocorticoid effect at the transcriptional level. However, in the presence of low concentrations of cortisol, all bile acids able to inhibit 11β-HSD2, including those unable to cause a direct MR translocation, induced an MR translocation (Fig. 2) and cortisol-mediated transactivation of the MMTV-lacZ.31, 32 Because low cortisol concentrations caused neither MR translocation (Fig. 2), nor MR-mediated transactivation in the absence of bile acids in cells expressing 11β-HSD2, it must be concluded that bile acids are able to enhance the intracellular availability of cortisol for MR activation by abrogating the gatekeeper effect of the 11β-HSD2 for the access of cortisol to the MR.

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Figure 2. HEK-293 cells were cotransfected with tagged 11β-HSD2 (green) and differentially tagged MR (red). In the absence of CDCA, the MR is localized in the cytoplasm and cortisol is unable to induce nuclear translocation (cytoplasm stains red), because cortisol is converted by the 11β-HSD2 into cortisone, a steroid without affinity for MR. In the presence of CDCA, cortisol induces a translocation of MR from the cytoplasm to the nucleus (nucleus stains red), an effect explained by the inhibition of 11β-HSD2 by CDCA. The 11β-HSD2 remains always anchored to the endoplasmic reticulum membrane.32

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Although conclusive, these mechanistic molecular biology data were generated in cells transfected with a plasmid expressing 11β-HSD2 and are therefore artificial. To assess the effect of bile acids in a system more close to reality, microdissected renal tubular segments from Sprague-Dawley rats were incubated with bile acids.33 In the MR-expressing cortical collecting duct, a principal renal target of mineralocorticoids, bile acids inhibited the 11β-HSD2 enzyme in a concentration-dependent manner.33 Interestingly, induction of cirrhosis by bile duct ligation decreased not only the activity of 11β-HSD2 by inhibiting the enzyme through increased concentrations of circulating bile acids, but also caused a consistent downregulation of the 11β-HSD2 enzyme at the transcriptional level.33, 34

At 6 weeks after bile duct ligation, when aldosterone concentrations were equal in ligated and control Munich-Wistar rats, the urinary sodium/potassium ratio was significantly lower and the apical targeting of epithelial sodium channel (ENaC) subunits in the cortical collecting duct was higher in cirrhotic than in noncirrhotic rats, indicating enhanced mineralocorticoid action in the cirrhotic animals.34, 35 In line with these observations made in rats with cirrhosis induced by bile duct ligation are observations in Munich-Wistar rats treated with carbon tetrachloride (CCl4).36 In the CCl4 model, an increased apical targeting of ENaC, including a mobility shift of gamma-ENaC from the 85-kD band to the 70-kD band, which is a representative finding of aldosterone effect in renal tubular cells, was associated with decreased 11β-HSD2 abundance.36 Although the decline in 11β-HSD2 in renal cirrhosis is a consistent finding, the effect on ENaC is not uniform in the various studies of cirrhosis induced in rats. This is probably best explained by the complex regulation of ENaC, the methodological difficulties linked with the assessment of the kinetics of the 3 constituents (alpha, beta, gamma) of this channel, and the apparent biphasic changes of ENaC abundance as a function of time during the induction of cirrhosis.34, 36–38 Besides ENaC, there is the thiazide-sensitive NaCl cotransporter, which is a second aldosterone-dependent transporter and thus presumably a 11β-HSD2-dependent transporter in the distal tubule.39 Whether this transporter is increased or decreased in cirrhotic rats is a matter of debate.37, 38, 40, 41

Renal sodium retention appears in at least some models before ascites is produced.2–4 Thus, a cross-talk between liver and kidney has to occur early in the cirrhotic disease state. It was proposed that bile acids might be the mediator of this cross-talk.32, 33 Urinary bile acid concentrations increased 25 times within 12 hours after bile duct ligation.33 Simultaneously, the renal activity of 11β-HSD2 as assessed by the urinary excretion ratio of (tetrahydrocorticosterone+5α-tetrahydrocorticosterone)/11-dehydro-tetrahydrocorticosterone declined significantly.33 Similar changes in the other direction were observed after removal of biliary obstruction in 12 patients.32 When cholestasis was corrected, bile acid concentrations normalized and urinary ratios of (tetrahydrocortisol+5α-tetrahydrocortisol)/tetrahydrocortisone and cortisol/cortisone declined by 50%.32 A decrease of this magnitude in the activity of 11β-HSD2 in patients with cholestasis confers cortisol-mediated mineralocorticoid action with renal sodium retention and potassium loss, a contention supported, first, by a doubling of the fractional urinary excretion of sodium following removal of biliary obstruction32 and, second, by the observation of similar changes in the above given urinary steroid ratios following administration of glycyrrhetinic acid, the model compound for 11β-HSD2 inhibition.19

Although investigations performed in vitro and in rats, as well as restricted observations in humans indicate that bile acids inhibit the 11β-HSD2 and by this mechanism induce a cortisol-mediated MR activation, the clinical significance of this mechanism for the formation of ascites deserves further investigations in humans. Ideally, the presumed increased ratio of 11β-hydroxy to 11-keto-glucocorticoids in MR-expressing renal tissue obtained from patients or at least from animals with high bile acids should be demonstrated, as it was previously shown in rats treated with a pharmacological inhibitor of 11β-HSD2.42 In healthy mammals, the overactivation of MR by an excess of aldosterone or by an excess of cortisol due to a loss of 11β-HSD2 activity causes excess fluid retention of about 1 to 2 L until a new steady state is achieved. This phenomenon of mineralocorticoid escape protects the human body from the formation of edema in some, but not all, situations of mineralocorticoid excess. The mineralocorticoid escape might be present or absent depending on the type and severity of the underlying liver disease and therefore possibly explains the peculiar observation that patients with primary biliary cirrhosis and sclerosing cholangitis, 2 disease states with pronounced elevations of bile acids, develop clinically significant ascites in a far more advanced stage than do patients with alcoholic or viral cirrhosis.

Other Mechanisms Reducing 11β-HSD2 Activity: Nitric Oxide, Angiotensin II, Shear Stress, Hypoxemia, and TNF-α

  1. Top of page
  2. Abstract
  3. Activation of MR by Cortisol
  4. Biology of 11β-HSD2
  5. Bile Acids Inhibit 11β-HSD2
  6. Other Mechanisms Reducing 11β-HSD2 Activity: Nitric Oxide, Angiotensin II, Shear Stress, Hypoxemia, and TNF-α
  7. Therapeutic Implications
  8. References

The primary mechanism responsible for deterioration of renal function in patients with liver failure is renal hypoperfusion. The extreme expression of this circulatory dysfunction is hepatorenal syndrome, which occurs in the setting of an intense stimulation of endogenous vasoconstrictors that overcomes the compensatory effect of the renal vasodilatory prostaglandins and nitric oxide.43, 44 In this type of liver failure there are at least 4 mechanisms present which are known to downregulate the activity of 11β-HSD2: nitric oxide, angiotensin II (ATII), hypoxemia, and shear stress. Nitric oxide donors inhibit transcription and activity of 11β-HSD2 in cell cultures derived from human placental trophoblasts and in the human bronchial epithelial cell line BEAS-2B.45, 46 ATII decreases the activity of 11β-HSD2 by an ATII receptor-dependent and a MAPK-dependent mechanism by inducing a destabilization of 11β-HSD2 mRNA.24, 47 These observations were made in vitro and await confirmation in vivo. Similarly, the downregulation of 11β-HSD2 by shear stress, a characteristic of extreme renal vasoconstriction which requires focal adhesion-cytoskeleton interactions, was established in vitro in human cells exhibiting endothelial features.48 On the other hand, the downregulation of 11β-HSD2 by hypoxia has been observed in cell culture experiments, ischemic rat kidneys, and humans exposed to hypoxemia at high altitude and is mediated by a MAPK-dependent induction of Egr-1.25, 49, 50

A peculiar feature of cirrhosis, with and without spontaneous bacterial peritonitis, is an inflammatory state that accounts at least in part for systemic hemodynamic derangements, including renal failure.51–53 The production of TNF-α, a central player in inflammatory reactions, has been shown to be markedly elevated in cirrhosis.51, 54, 55 TNF-α substantially reduces the expression of 11β-HSD2, a contention supported by several lines of evidence. First, Takahashi et al. reported a decreased 11β-HSD2 expression in the mineralocorticoid responsive colonic mucosa of patients with inflammatory bowel disease.56 Second, Heiniger et al. showed that TNF-α diminishes the expression and activity of 11β-HSD2 in renal epithelial LLC-PK1 cells by a MAPK-dependent mechanism and demonstrated that TNF-α uses this mechanism to increase the intracellular availability of glucocorticoids, an effect evident in LLC-PK1 cells stably transfected with a reporter gene controlled by a promoter containing glucocorticoid response elements (GREs).26 Third, Kostadinova et al. deciphered the transcriptional regulation of 11β-HSD2 by TNF-α and proved that the downregulation is explained by coordinate binding to the 11β-HSD2 promoter of Egr-1 and NF-κB homodimer p50/p50 which lack a transcriptional activation domain; in addition, the researchers observed a diminished mRNA abundance and activity of 11β-HSD2 in kidneys from transgenic mice overexpressing TNF-α.57

Thus, TNF-α and hypoxia enhance the availability of biologically active cortisol in mineralocorticoid responsive tissues by reducing the expression of 11β-HSD2. In addition, as previously shown, TNF-α enhances the formation of biologically active glucocorticoids at the site of action by stimulating the reductase activity of 11β-HSD1 (Fig. 1).58 This increased intracellular availability of glucocorticoids in cirrhosis as a consequence of inflammation and hypoxia is a finding in line with the mammalian stress response system59 and might contribute not only to overcoming unwanted effects in inflammatory or hypoxemic stress as discussed,57, 58 but also to enhancing renal sodium retention by inappropriate access of glucocorticoids to epithelial MR. The latter effect might be warranted at least in part in patients with cirrhosis because TNF-α has some potential to inhibit ATII-induced and ACTH-induced expression of aldosterone synthase.60, 61

Therapeutic Implications

  1. Top of page
  2. Abstract
  3. Activation of MR by Cortisol
  4. Biology of 11β-HSD2
  5. Bile Acids Inhibit 11β-HSD2
  6. Other Mechanisms Reducing 11β-HSD2 Activity: Nitric Oxide, Angiotensin II, Shear Stress, Hypoxemia, and TNF-α
  7. Therapeutic Implications
  8. References

The consequences derived from the cortisol-activated MR in cirrhosis are based on pathophysiological reasoning and are not evidence-based. A reduced activity of 11β-HSD2 confers salt sensitivity.62 Thus, sodium restriction is the first and most important therapeutic step. If sodium restriction is not successful, then a diuretic is required, most likely spironolactone or eplerenone, 2 agents that compete with cortisol and aldosterone for binding to the MR. Amiloride has diuretic action more downstream from the MR, at the level of ENaC. This agent is not frequently prescribed to patients with cirrhosis presumably over concerns of potency.63 Most patients also require a more proximal acting diuretic, and furosemide is traditionally prescribed. At high doses, furosemide inhibits 11β-HSD264, which has been shown to be associated with an enhanced calciuria.65 Thus, although not commonly used in clinical practice, a calcium-sparing potent thiazide such as metolazone might be a more logical candidate in patients with a preserved glomerular filtration rate, especially when the activation of the aldosterone-sensitive NaCl cotransporter in cirrhosis is confirmed in future studies.

Removal of the mechanisms causing a reduced 11β-HSD2 activity in patients with cirrhosis, such as bile acids, TNF-α, nitric oxide, ATII, hypoxia, or shear stress, is only partially possible. Removal of bile acids would be the most efficient strategy to enhance 11β-HSD2 in patients with liver failure, a strategy only applicable in rare subjects with biliary obstruction.32 Pharmacological interventions with beta-blocking agents reduce release of renin, and angiotensin-converting enzyme inhibitors or ATII receptor blocking drugs alleviate ATII-mediated and possibly shear stress-mediated downregulation of 11β-HSD2.24, 48, 66 Whether converting enzyme inhibitors and ATII receptor blockers are useful xenobiotics in some patients with cirrhosis is an unresolved issue. Prevention or aggressive treatment of infection complications, a major cause of the development of hepatorenal syndrome, allows reduction of the release of TNF-α or nitric oxide and possibly hypoxemia, 3 mechanisms known to impair 11β-HSD2 activity.25, 45, 57 The factors contributing to inhibition and/or downregulation of the 11β-HSD2 should probably still be avoided and/or removed, when the kidney has failed; Serra et al. showed that inhibition of 11β-HSD2 by glycyrrhetinic acid diminishes serum potassium concentrations, most likely by interfering with the MR-dependent Na+/K+ exchange in the 11β-HSD2 expressing colon epithelia, even in anuric patients.67 Thus, licorice, an ingredient present in many alcoholic beverages and candies, should be avoided in patients with cirrhosis.


  1. Top of page
  2. Abstract
  3. Activation of MR by Cortisol
  4. Biology of 11β-HSD2
  5. Bile Acids Inhibit 11β-HSD2
  6. Other Mechanisms Reducing 11β-HSD2 Activity: Nitric Oxide, Angiotensin II, Shear Stress, Hypoxemia, and TNF-α
  7. Therapeutic Implications
  8. References
  • 1
    Schrier RW. Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy (2). N Engl J Med 1988; 319: 11271134.
  • 2
    Levy M, Wexler MJ. Renal sodium retention and ascites formation in dogs with experimental cirrhosis but without portal hypertension or increased splanchnic vascular capacity. J Lab Clin Med 1978; 91: 520536.
  • 3
    Levy M, Allotey JB. Temporal relationships between urinary salt retention and altered systemic hemodynamics in dogs with experimental cirrhosis. J Lab Clin Med 1978; 92: 560569.
  • 4
    Wensing G, Sabra R, Branch RA. The onset of sodium retention in experimental cirrhosis in rats is related to a critical threshold of liver function. HEPATOLOGY 1990; 11: 779786.
  • 5
    Jimenez W, Martinez-Pardo A, Arroyo V, Bruix J, Rimola A, Gaya J, et al. Temporal relationship between hyperaldosteronism, sodium retention and ascites formation in rats with experimental cirrhosis. HEPATOLOGY 1985; 5: 245250.
  • 6
    Bernardi M, Di Marco C, Trevisani F, Fornale L, Andreone P, Cursaro C, et al. Renal sodium retention during upright posture in preascitic cirrhosis. Gastroenterology 1993; 105: 188193.
  • 7
    Cardenas A, Arroyo V. Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of ascites. Best Pract Res Clin Endocrinol Metab 2003; 17: 607622.
  • 8
    Salo J, Gines A, Anibarro L, Jimenez W, Bataller R, Claria J, et al. Effect of upright posture and physical exercise on endogenous neurohormonal systems in cirrhotic patients with sodium retention and normal supine plasma renin, aldosterone, and norepinephrine levels. HEPATOLOGY 1995; 22: 479487.
  • 9
    Bernardi M. Renal sodium retention in preascitic cirrhosis: expanding knowledge, enduring uncertainties. HEPATOLOGY 2002; 35: 15441547.
  • 10
    Wilkinson SP, Jowett TP, Slater JD, Arroyo V, Moodie H, Williams R. Renal sodium retention in cirrhosis: relation to aldosterone and nephron site. Clin Sci (Lond) 1979; 56: 169177.
  • 11
    Decaux G, Hanson B, Cauchie P, Bosson D, Unger J. Relationship between aldosterone and sodium, potassium, and uric acid clearance in cirrhosis with and without ascites. Nephron 1986; 44: 226229.
  • 12
    Trevisani F, Bernardi M, De Palma R, Pancione L, Capani F, Baraldini M, et al. Circadian variation in renal sodium and potassium handling in cirrhosis. The role of aldosterone, cortisol, sympathoadrenergic tone, and intratubular factors. Gastroenterology 1989; 96: 11871198.
  • 13
    Pearce D, Bhargava A, Cole TJ. Aldosterone: its receptor, target genes, and actions. Vitam Horm 2003; 66: 2976.
  • 14
    Verrey F. Transcriptional control of sodium transport in tight epithelial by adrenal steroids. J Membr Biol 1995; 144: 93110.
  • 15
    Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 1988; 242: 583585.
  • 16
    Edwards CR, Stewart PM, Burt D, Brett L, McIntyre MA, Sutanto WS, et al. Localisation of 11 beta-hydroxysteroid dehydrogenase–tissue specific protector of the mineralocorticoid receptor. Lancet 1988; 2: 986989.
  • 17
    Odermatt A, Dick B, Arnold P, Zaehner T, Plueschke V, Deregibus MN, et al. A mutation in the cofactor-binding domain of 11beta-hydroxysteroid dehydrogenase type 2 associated with mineralocorticoid hypertension. J Clin Endocrinol Metab 2001; 86: 12471252.
  • 18
    Wilson RC, Dave-Sharma S, Wei JQ, Obeyesekere VR, Li K, Ferrari P, et al. A genetic defect resulting in mild low-renin hypertension. Proc Natl Acad Sci U S A 1998; 95: 1020010205.
  • 19
    Ferrari P, Sansonnens A, Dick B, Frey FJ. In vivo 11beta-HSD-2 activity: variability, salt-sensitivity, and effect of licorice. Hypertension 2001; 38: 13301336.
  • 20
    Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol 1994; 105: R11R17.
  • 21
    Odermatt A, Arnold P, Stauffer A, Frey BM, Frey FJ. The N-terminal anchor sequences of 11beta-hydroxysteroid dehydrogenases determine their orientation in the endoplasmic reticulum membrane. J Biol Chem 1999; 274: 2876228770.
  • 22
    Nawrocki AR, Goldring CE, Kostadinova RM, Frey FJ, Frey BM. In vivo footprinting of the human 11beta-hydroxysteroid dehydrogenase type 2 promoter: evidence for cell-specific regulation by Sp1 and Sp3. J Biol Chem 2002; 277: 1464714656.
  • 23
    Alikhani-Koopaei R, Fouladkou F, Frey FJ, Frey BM. Epigenetic regulation of 11 beta-hydroxysteroid dehydrogenase type 2 expression. J Clin Invest 2004; 114: 11461157.
  • 24
    Lanz B, Kadereit B, Ernst S, Shojaati K, Causevic M, Frey BM, et al. Angiotensin II regulates 11beta-hydroxysteroid dehydrogenase type 2 via AT2 receptors. Kidney Int 2003; 64: 970977.
  • 25
    Heiniger CD, Kostadinova RM, Rochat MK, Serra A, Ferrari P, Dick B, et al. Hypoxia causes down-regulation of 11 beta-hydroxysteroid dehydrogenase type 2 by induction of Egr-1. FASEB J 2003; 17: 917919.
  • 26
    Heiniger CD, Rochat MK, Frey FJ, Frey BM. TNF-alpha enhances intracellular glucocorticoid availability. FEBS Lett 2001; 507: 351356.
  • 27
    Hierholzer K, Siebe H, Fromm M. Inhibition of 11 beta-hydroxysteroid dehydrogenase and its effect on epithelial sodium transport. Kidney Int 1990; 38: 673678.
  • 28
    Perschel FH, Buhler H, Hierholzer K. Bile acids and their amidates inhibit 11 beta-hydroxysteroid dehydrogenase obtained from rat kidney. Pfluegers Arch 1991; 418: 538543.
  • 29
    Agarwal AK, Monder C, Eckstein B, White PC. Cloning and expression of rat cDNA encoding corticosteroid 11 beta-dehydrogenase. J Biol Chem 1989; 264: 1893918943.
  • 30
    Escher G, Nawrocki A, Staub T, Vishwanath BS, Frey BM, Reichen J, et al. Down-regulation of hepatic and renal 11 beta-hydroxysteroid dehydrogenase in rats with liver cirrhosis. Gastroenterology 1998; 114: 175184.
  • 31
    Stauffer AT, Rochat MK, Dick B, Frey FJ, Odermatt A. Chenodeoxycholic acid and deoxycholic acid inhibit 11 beta-hydroxysteroid dehydrogenase type 2 and cause cortisol-induced transcriptional activation of the mineralocorticoid receptor. J Biol Chem 2002; 277: 2628626292.
  • 32
    Quattropani C, Vogt B, Odermatt A, Dick B, Frey BM, Frey FJ. Reduced activity of 11 beta-hydroxysteroid dehydrogenase in patients with cholestasis. J Clin Invest 2001; 108: 12991305.
  • 33
    Ackermann D, Vogt B, Escher G, Dick B, Reichen J, Frey BM, et al. Inhibition of 11beta-hydroxysteroid dehydrogenase by bile acids in rats with cirrhosis. HEPATOLOGY 1999; 30: 623629.
  • 34
    Kim SW, Wang W, Sassen MC, Choi KC, Han JS, Knepper MA, et al. Biphasic changes of epithelial sodium channel abundance and trafficking in common bile duct ligation-induced liver cirrhosis. Kidney Int 2006; 69: 8998.
  • 35
    Masilamani S, Kim GH, Mitchell C, Wade JB, Knepper MA. Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney. J Clin Invest 1999; 104: R19R23.
  • 36
    Kim SW, Schou UK, Peters CD, de Seigneux S, Kwon TH, Knepper MA, et al. Increased apical targeting of renal epithelial sodium channel subunits and decreased expression of type 2 11beta-hydroxysteroid dehydrogenase in rats with CCl4-induced decompensated liver cirrhosis. J Am Soc Nephrol 2005; 16: 31963210.
  • 37
    Fernandez-Llama P, Ageloff S, Fernandez-Varo G, Ros J, Wang X, Garra N, et al. Sodium retention in cirrhotic rats is associated with increased renal abundance of sodium transporter proteins. Kidney Int 2005; 67: 622630.
  • 38
    Yu Z, Serra A, Sauter D, Loffing J, Ackermann D, Frey FJ, et al. Sodium retention in rats with liver cirrhosis is associated with increased renal abundance of NaCl cotransporter (NCC). Nephrol Dial Transplant 2005; 20: 18331841.
  • 39
    Kim GH, Masilamani S, Turner R, Mitchell C, Wade JB, Knepper MA. The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. Proc Natl Acad Sci U S A 1998; 95: 1455214557.
  • 40
    Ecelbarger CA. Role of the aldosterone-sensitive distal nephron in the sodium retention associated with liver cirrhosis. Kidney Int 2006; 69: 1012.
  • 41
    Fernandez-Llama P, Jimenez W, Bosch-Marce M, Arroyo V, Nielsen S, Knepper MA. Dysregulation of renal aquaporins and Na-Cl cotransporter in CCl4-induced cirrhosis. Kidney Int 2000; 58: 216228.
  • 42
    Escher G, Frey FJ, Frey BM. 11 beta-Hydroxysteroid dehydrogenase accounts for low prednisolone/prednisone ratios in the kidney. Endocrinology 1994; 135: 101106.
  • 43
    Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Gines P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. HEPATOLOGY 2005; 42: 439447.
  • 44
    Arroyo V, Guevara M, Gines P. Hepatorenal syndrome in cirrhosis: pathogenesis and treatment. Gastroenterology 2002; 122: 16581676.
  • 45
    Sun K, Yang K, Challis JR. Differential regulation of 11 beta-hydroxysteroid dehydrogenase type 1 and 2 by nitric oxide in cultured human placental trophoblast and chorionic cell preparation. Endocrinology 1997; 138: 49124920.
  • 46
    Suzuki S, Tsubochi H, Ishibashi H, Matsuda Y, Suzuki T, Krozowski ZS, et al. Inflammatory mediators down-regulate 11beta-hydroxysteroid dehydrogenase type 2 in a human lung epithelial cell line BEAS-2B and the rat lung. Tohoku J Exp Med 2005; 207: 293301.
  • 47
    Riddle MC, McDaniel PA. Renal 11 beta-hydroxysteroid dehydrogenase activity is enhanced by ramipril and captopril. J Clin Endocrinol Metab 1994; 78: 830834.
  • 48
    Lanz CB, Causevic M, Heiniger C, Frey FJ, Frey BM, Mohaupt MG. Fluid Shear Stress Reduces 11ss-Hydroxysteroid Dehydrogenase Type 2. Hypertension 2001; 37: 160169.
  • 49
    Murotsuki J, Challis JR, Han VK, Fraher LJ, Gagnon R. Chronic fetal placental embolization and hypoxemia cause hypertension and myocardial hypertrophy in fetal sheep. Am J Physiol 1997; 272: R201R207.
  • 50
    Schumacher M, Frey FJ, Montani JP, Dick B, Frey BM, Ferrari P. Salt-sensitivity of blood pressure and decreased 11beta-hydroxysteroid dehydrogenase type 2 activity after renal transplantation. Transplantation 2002; 74: 6672.
  • 51
    Ruiz-del-Arbol L, Urman J, Fernandez J, Gonzalez M, Navasa M, Monescillo A, et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. HEPATOLOGY 2003; 38: 12101218.
  • 52
    Navasa M, Follo A, Filella X, Jimenez W, Francitorra A, Planas R, et al. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality. HEPATOLOGY 1998; 27: 12271232.
  • 53
    Vishwanath BS, Frey FJ, Escher G, Reichen J, Frey BM. Liver cirrhosis induces renal and liver phospholipase A2 activity in rats. J Clin Invest 1996; 98: 365371.
  • 54
    Tazi KA, Quioc JJ, Saada V, Bezeaud A, Lebrec D, Moreau R. Upregulation of TNF-alpha production signaling pathways in monocytes from patients with advanced cirrhosis: possible role of Akt and IRAK-M. J Hepatol 2006; 45: 280289.
  • 55
    Odeh M, Sabo E, Srugo I, Oliven A. Relationship between tumor necrosis factor-alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure. Ann Med 2005; 37: 603612.
  • 56
    Takahashi KI, Fukushima K, Sasano H, Sasaki I, Matsuno S, Krozowski ZS, et al. Type II 11beta-hydroxysteroid dehydrogenase expression in human colonic epithelial cells of inflammatory bowel disease. Dig Dis Sci 1999; 44: 25162522.
  • 57
    Kostadinova RM, Nawrocki AR, Frey FJ, Frey BM. Tumor necrosis factor alpha and phorbol 12-myristate-13-acetate down-regulate human 11beta-hydroxysteroid dehydrogenase type 2 through p50/p50 NF-kappaB homodimers and Egr-1. FASEB J 2005; 19: 650652.
  • 58
    Escher G, Galli I, Vishwanath BS, Frey BM, Frey FJ. Tumor necrosis factor alpha and interleukin 1beta enhance the cortisone/cortisol shuttle. J Exp Med 1997; 186: 189198.
  • 59
    Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 1984; 5: 2544.
  • 60
    Natarajan R, Ploszaj S, Horton R, Nadler J. Tumor necrosis factor and interleukin-1 are potent inhibitors of angiotensin-II-induced aldosterone synthesis. Endocrinology 1989; 125: 30843089.
  • 61
    Takeda Y, Miyamori I, Yoneda T, Hatakeyama H, Inaba S, Furukawa K, et al. Regulation of aldosterone synthase in human vascular endothelial cells by angiotensin II and adrenocorticotropin. J Clin Endocrinol Metab 1996; 81: 27972800.
  • 62
    Lovati E, Ferrari P, Dick B, Jostarndt K, Frey BM, Frey FJ, et al. Molecular basis of human salt sensitivity: the role of the 11beta-hydroxysteroid dehydrogenase type 2. J Clin Endocrinol Metab 1999; 84: 37453749.
  • 63
    Angeli P, Dalla Pria M, De Bei E, Albino G, Caregaro L, Merkel C, et al. Randomized clinical study of the efficacy of amiloride and potassium canrenoate in nonazotemic cirrhotic patients with ascites. HEPATOLOGY 1994; 19: 7279.
  • 64
    Fuster D, Escher G, Vogt B, Ackermann D, Dick B, Frey BM, et al. Furosemide inhibits 11beta-hydroxysteroid dehydrogenase type 2. Endocrinology 1998; 139: 38493854.
  • 65
    Ferrari P, Bianchetti MG, Sansonnens A, Frey FJ. Modulation of renal calcium handling by 11 beta-hydroxysteroid dehydrogenase type 2. J Am Soc Nephrol 2002; 13: 25402546.
  • 66
    Wong F, Liu P, Blendis L. The mechanism of improved sodium homeostasis of low-dose losartan in preascitic cirrhosis. HEPATOLOGY 2002; 35: 14491458.
  • 67
    Serra A, Uehlinger DE, Ferrari P, Dick B, Frey BM, Frey FJ, et al. Glycyrrhetinic acid decreases plasma potassium concentrations in patients with anuria. J Am Soc Nephrol 2002; 13: 191196.
  • 68
    Frey FJ, Odermatt A, Frey BM. Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr Opin Nephrol Hypertens 2004; 13: 451458.