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

Abstract

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...

ENaC activity in collecting ducts modulates NCC in cirrhotic mice

“…We showed previously, that bile duct-ligated mice developed ascites concomitantly to Na,K-ATPase stimulation in cortical collecting ducts exclusively [1]. Underlining the role of the aldosterone sensitive distal nephron in ascites development, studies performed with rats showed an increased apical targeting of ENaC in ascitic animals [20,21].…”

The physiological impact of the serum and glucocorticoid-inducible kinase SGK1

“…SGK1-dependent renal salt retention favor the development of edema during treatment with PPARγ agonists [166] or in nephrotic syndrome [135]. Furthermore, increased SGK1 expression has been found during ascites formation in cirrhotic rats [167]. …”

A novel model of CCl4-induced cirrhosis with ascites in the mouse

“…Peritoneal fluid was always present when hepatotoxins were administered via the intraperitoneal route, but extensive intra-abdominal adhesions occurred in the majority of mice precluding a correct evaluation of ascites. An alternative model of cirrhosis is represented by BDL, which is also associated to a high mortality rate and induces histological changes that are quite different from those observed in the human form of disease [11][12][13]. Although the BDL model ultimately leads to decompensation, ascites can scarcely be assessed due to the occurrence of post-surgical intraperitoneal adhesions [11].…”