Sodium retention in rats with liver cirrhosis is associated with increased renal abundance of NaCl cotransporter (NCC)

Yu, Zhenrong; Serra, Andreas L.; Sauter, Daniel; Loffing, Johannes; Ackermann, Daniel; Frey, Felix J.; Frey, Brigitte M.; Vogt, Bruno

doi:10.1093/ndt/gfh916

Cited by 13 publications

(10 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

mentioning

confidence: 96%

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

et al. 2007

Self Cite

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 96%

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

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…Loss-of-function mutations of NCC (Gitelman syndrome) cause renal salt wasting with hypotension, hypokalemic alkalosis, and hypocalciuria, 3 whereas increased NCC activity because of mutations within the NCC-regulating with-no-lysine kinase 1 (WNK1) or WNK4 (familial hyperkalemic hypertension) are associated with severe salt-sensitive hypertension, hyperkalemia, metabolic acidosis, and hypercalciuria. 4 Increased NCC expression has been linked to renal Na + retention in liver cirrhosis, 5 diabetes mellitus, 6 b-adrenergic stimulation, 7 and immunosuppressive treatment. 8 The clinical significance of the DCT is also emphasized by clinical trials that confirmed the DCT as an important target for antihypertensive therapy.…”

mentioning

confidence: 99%

Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension

Picard

Trompf

Yang

et al. 2014

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

The thiazide-sensitive NaCl cotransporter (NCC) of the renal distal convoluted tubule (DCT) controls ion homeostasis and arterial BP. Loss-of-function mutations of NCC cause renal salt wasting with arterial hypotension (Gitelman syndrome). Conversely, mutations in the NCC-regulating WNK kinases or kelchlike 3 protein cause familial hyperkalemic hypertension. Here, we performed automated sorting of mouse DCTs and microarray analysis for comprehensive identification of novel DCT-enriched gene products, which may potentially regulate DCT and NCC function. This approach identified protein phosphatase 1 inhibitor-1 (I-1) as a DCT-enriched transcript, and immunohistochemistry revealed I-1 expression in mouse and human DCTs and thick ascending limbs. In heterologous expression systems, coexpression of NCC with I-1 increased thiazide-dependent Na + uptake, whereas RNAi-mediated knockdown of endogenous I-1 reduced NCC phosphorylation. Likewise, levels of phosphorylated NCC decreased by approximately 50% in I-1 (I-1 2/2 ) knockout mice without changes in total NCC expression. The abundance and phosphorylation of other renal sodium-transporting proteins, including NaPi-IIa, NKCC2, and ENaC, did not change, although the abundance of pendrin increased in these mice. The abundance, phosphorylation, and subcellular localization of SPAK were similar in wild-type (WT) and I-1 2/2 mice. Compared with WT mice, I-1 2/2 mice exhibited significantly lower arterial BP but did not display other metabolic features of NCC dysregulation. Thus, I-1 is a DCT-enriched gene product that controls arterial BP, possibly through regulation of NCC activity.

show abstract

“…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][37][38] Besides ENaC, there is the thiazide-sensitive NaCl cotransporter, which is a second aldosterone-dependent transporter and thus presumably a 11␤-HSD2-dependent transporter in the distal tubule. 39 Whether this transporter is increased or decreased in cirrhotic rats is a matter of debate.…”

Section: Biology Of 11␤-hsd2mentioning

confidence: 99%

“…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][3][4] Thus, a cross-talk between liver and kidney has to occur early in the cirrhotic disease state.…”

Section: Biology Of 11␤-hsd2mentioning

confidence: 99%

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

Frey

2006

Hepatology

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Sodium retention in rats with liver cirrhosis is associated with increased renal abundance of NaCl cotransporter (NCC)

Abstract: Enhanced abundance of NCC was observed in the initial stage after BDL, followed by a marked decrease. ENaC transcription, translation or cell surface abundance was not increased after BDL.

Cited by 13 publications

References 22 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?

Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension

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

Contact Info

Product

Resources

About