Abstract
ObjectiveAldosterone, one of the main peptides in renin angiotensin aldosterone system (RAAS), has been suggested to mediate liver fibrosis and portal hypertension. Spironolactone, an aldosterone antagonist, has beneficial effect on hyperdynamic circulation in clinical practice. However, the mechanisms remain unclear. The present study aimed to investigate the role of spionolactone on liver cirrhosis and portal hypertension.MethodsLiver cirrhosis was induced by bile duct ligation (BDL). Spironolactone was administered orally (20 mg/kg/d) after bile duct ligation was performed. Liver fibrosis was assessed by histology, Masson's trichrome staining, and the measurement of hydroxyproline and type I collagen content. The activation of HSC was determined by analysis of alpha smooth muscle actin (α-SMA) expression. Protein expressions and protein phosphorylation were determined by immunohistochemical staining and Western blot analysis, Messenger RNA levels by quantitative real time polymerase chain reaction (Q-PCR). Portal pressure and intrahepatic resistance were examined in vivo.ResultsTreatment with spironolactone significantly lowered portal pressure. This was associated with attenuation of liver fibrosis, intrahepatic resistance and inhibition of HSC activation. In BDL rat liver, spironolactone suppressed up-regulation of proinflammatory cytokines (TNFα and IL-6). Additionally, spironolactone significantly decreased ROCK-2 activity without affecting expression of RhoA and Ras. Moreover, spironolactone markedly increased the levels of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS and the activity of NO effector- protein kinase G (PKG) in the liver.ConclusionSpironolactone lowers portal hypertension by improvement of liver fibrosis and inhibition of intrahepatic vasoconstriction via down-regulating ROCK-2 activity and activating NO/PKG pathway. Thus, early spironolactone therapy might be the optional therapy in cirrhosis and portal hypertension.
Highlights
In cirrhosis, increased intrahepatic resistance is the primary event causing portal hypertension [1,2,3]
Treatment with spironolactone significantly lowered portal pressure. This was associated with attenuation of liver fibrosis, intrahepatic resistance and inhibition of hepatic stellate cells (HSCs) activation
Spironolactone markedly increased the levels of endothelial nitric oxide synthase, phosphorylated eNOS and the activity of NO effector- protein kinase G (PKG) in the liver
Summary
In cirrhosis, increased intrahepatic resistance is the primary event causing portal hypertension [1,2,3]. Both intrahepatic fibrosis and imbalance between vasoconstrictor and vasodilator mediators contribute to increased resistance [4,5]. Aldosterone, one of the main peptides in the RAAS, has been suggested to mediate inflammation, oxidative stress, endothelial dysfunction and fibrosis [6,7]. Existing studies of aldosterone inhibitors have showed that the mineralocorticoid receptor (MR) antagonist reduces fibrogenesis and lowers portal hypertension [8,9]. The molecular mechanisms by which spironolactone induces these effects remain unclear
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