Increased Apical Targeting of Renal Epithelial Sodium Channel Subunits and Decreased Expression of Type 2 11β-Hydroxysteroid Dehydrogenase in Rats with CCl4-Induced Decompensated Liver Cirrhosis

Kim, Soo Wan; Schou, Uffe K.; Peters, Christian Daugaard; Seigneux, Sophie de; Kwon, Tae‐Hwan; Knepper, Mark A.; Jonassen, Thomas E. N.; Frøki, Jørgen; Nielsén, Sören

doi:10.1681/asn.2004080721

Cited by 36 publications

(26 citation statements)

References 41 publications

(42 reference statements)

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“…34,36,38 Curiously, however, no change in Na ϩ ,K ϩ -ATPase activity was observed in distal convoluted tubule (DCT), connecting tubule (CNT) and outer medullary collecting duct (OMCD), the other targets sites of aldosterone, although increased apical targeting of ENaC (CNT and OMCD) or overexpression of the sodium chloride cotransporter (DCT) were previously reported in cirrhotic animals. 34,36,38 This suggests that, except in the CCD, the stimulatory effect of aldosterone on apical sodium transporters is counterbalanced by a post MR mechanism that prevents induction of Na ϩ ,K ϩ -ATPase and thereby limits sodium retention. Na ϩ ,K ϩ -ATPase was not altered in the medullary and cortical thick ascending limb of Henle's loop (MTAL and CTAL), although this nephron segment was proposed as a main site of sodium retention in BDL rats.…”

Section: Discussionmentioning

confidence: 99%

“…33 Along with the uncertainties concerning the role aldosterone and MR, there is no consensus either on the renal site of sodium retention. Although several reports in experimental models of cirrhosis show that sodium retention originates along the aldosterone-sensitive nephron segments, 29,32,[34][35][36][37][38][39] other reports concluded to the thick ascending limb of Henle's loop as the main site of sodium retention in rat models. 40,41 The present study aimed at (1) localizing the site of sodium retention along the nephron, and (2) at determining the role of aldosterone and MR in sodium retention.…”

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confidence: 97%

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Sodium retention and ascites formation in a cholestatic mice model: Role of aldosterone and mineralocorticoid receptor?

et al. 2007

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Renal sodium retention in experimental liver cirrhosis originates from the distal nephron sensitive to aldosterone. The aims of this study were to (1) determine the exact site of sodium retention along the aldosterone-sensitive distal nephron, and (2) to evaluate the role of aldosterone and mineralocorticoid receptor activation in this process. Liver cirrhosis was induced by bile duct ligation in either adrenalintact or corticosteroid-clamped mice. Corticosteroid-clamp was achieved through adrenalectomy and corticosteroid supplementation with aldosterone and dexamethasone via osmotic minipumps. 24-hours renal sodium balance was evaluated in metabolic cages. Activity and expression of sodiumand potassium-dependent adenosine triphosphatase were determined in microdissected segments of nephron. Within 4-5 weeks, cirrhosis induced sodium retention in adrenal-intact mice and formation of ascites in 50% of mice. At that time, sodium-and potassium-dependent adenosine triphosphatase activity increased specifically in cortical collecting ducts. Hyperaldosteronemia was indicated by increases in urinary aldosterone excretion and in sgk1 (serum-and glucocorticoid-regulated kinase 1) mRNA expression in collecting ducts. Corticosteroid-clamp prevented induction of sgk1 but not cirrhosis-induced sodium retention, formation of ascites and stimulation of sodium-and potassiumdependent adenosine triphosphatase activity and expression (mRNA and protein) in collecting duct. These findings demonstrate that sodium retention in cirrhosis is independent of hyperaldosteronemia and of the activation of mineralocorticoid receptor. Conclusion: Bile duct ligation in mice induces cirrhosis which, within 4-5 weeks, leads to the induction of sodium-and potassium-dependent adenosine triphosphatase in cortical collecting ducts, to renal sodium retention and to the formation of ascites. Sodium retention, ascites formation and induction of sodium-and potassium-dependent adenosine triphosphatase are independent of the activation of mineralocorticoid receptors by either aldosterone or glucocorticoids. (HEPATOLOGY 2007;46:173-179.) See Editorial on Page 9 P atients with liver cirrhosis and portal hypertension develop renal sodium retention which promotes formation of ascites and peripheral edema. The "underfill theory" initially attributed sodium retention to secondary hyperaldosteronism accounted for by renal hypoperfusion brought about by intraabdominal fluid sequestration. 1 However, the underfill theory cannot explain the early phase of cirrhosis as sodium retention may precedes formation of ascites. 2-7 Thus, the "overflow theory" postulated that edema and ascites formation resulted from primary renal sodium retention promoting plasma volume expansion. 8 This theory is supported by the fact that abolishing portal hypertension in cirrhotic dogs by sideto-side portocaval shunt prevented ascites formation but not sodium retention. 5,6 Later, the "revised underfill theory" proposed that peripheral arterial vasodilatation leading to decreased effec...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

Sodium retention and ascites formation in a cholestatic mice model: Role of aldosterone and mineralocorticoid receptor?

et al. 2007

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“…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 (CCl 4 ). 36 In the CCl 4 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 11␤-HSD2 abundance. 36 Although the decline in 11␤-HSD2 in renal cirrhosis is a consistent finding, the effect on ENaC is not uniform in the various studies of cirrhosis induced in rats.…”

Section: Biology Of 11␤-hsd2mentioning

confidence: 93%

Impaired 11β-hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis: Hypothesis or fact?

Frey

2006

Hepatology

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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...

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“…Immunolabeling was performed on sections from paraffin-embedded preparations (2 μm thickness) using methods described previously (Kim et al, 2005;Kim et al, 2006). Affinity-purified rabbit polyclonal antibodies were used against the neutral endopeptidase (NEP, Santa Cruz; CA, USA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…The urinary sodium excretion may change according to the different stages of nephrotic syndrome (Deschenes et al, 2000) and liver cirrhosis (Kim et al, 2005;Kim et al, 2006). The time course of PAN-induced nephrosis consists of urinary sodium retention, followed by natriuresis that is comparable to control (Deschenes et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Changes of Atrial Natriuretic Peptide System in Rats with Puromycin Aminonucleoside-Induced Nephrotic Syndrome

Bae

Lee

Kwon

et al. 2009

Korean J Physiol Pharmacol

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Increased Apical Targeting of Renal Epithelial Sodium Channel Subunits and Decreased Expression of Type 2 11β-Hydroxysteroid Dehydrogenase in Rats with CCl4-Induced Decompensated Liver Cirrhosis

Cited by 36 publications

References 41 publications

Sodium retention and ascites formation in a cholestatic mice model: Role of aldosterone and mineralocorticoid receptor?

Sodium retention and ascites formation in a cholestatic mice model: Role of aldosterone and mineralocorticoid receptor?

Impaired 11β-hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis: Hypothesis or fact?

Changes of Atrial Natriuretic Peptide System in Rats with Puromycin Aminonucleoside-Induced Nephrotic Syndrome

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