Impaired 11β‐hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis

Abstract

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 11␤-hydroxysteroid dehydrogenase type 2, an enzyme protecting the MR from promiscuous activation by cortisol in healthy mammalians. (HEPATOLOGY 2006;44:795-801.) R enal 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 peptides 2-8 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 load 7 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][11][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 MRactivating 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 11␤-hydroxysteroid dehydrogenase type 2 (11␤-HSD2), which allows promiscuous activation of MR by the glucocorticoid cortisol. Activation of MR by CortisolInitially 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 cor...

Sodium retention and ascites formation in a cholestatic mice model

“…Because chenodeoxycholic acid is increased in cholestasis and dosedependently inhibits 11␤-HSD2 activity in CCD allowing activation of the MR by endogenous corticosterone, 29,48 this pathway was proposed as the initial stimulator of sodium retention during liver cirrhosis. 32,49,50 However, present data in corticosteroid-clamped BDL mice demonstrate that inhibition of 11␤-HSD2 activity is not essential for sodium retention in liver cirrhosis. First, activation of MR should stimulate Na ϩ ,K ϩ -ATPase and induce over-expression of sgk1 and ENaC mRNAs all along the distal nephron and not specifically in the CCD.…”

Relative adrenal insufficiency in mice deficient in 5α-reductase 1

“…In addition, recent observations have indicated that a key contribution results from alterations in the enzymatic clearance of cortisol. In liver disease, inactivation of cortisol by the enzymes 5β-reductase ( Akr1d1 ) and 11β-hydroxysteroid dehydrogenase type 2 ( Hsd11b2 ; Frey 2006, McNeilly et al . 2010) is impaired.…”

Tumor necrosis factor-α upregulates 11β-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-β in HepG2 cells

“…p38 mitogen-activated protein kinase; chromatin immunoprecipitation; RNA interference IN MAMMALIAN TISSUES, THE SENSITIVITY to glucocorticoids depends not only on circulating glucocorticoid levels, but also on glucocorticoid receptor expression and intracellular availability of active glucocorticoid, which is determined by 11␤-hydroxysteroid dehydrogenase enzymes (11␤-HSD) (21,22). Two enzymes play a role in this process, 11␤-HSD1 and 11␤-HSD2.…”