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Spironolactone lowers portal hypertension by inhibiting liver fibrosis, ROCK-2 activity and activating NO/PKG pathway in the bile-duct-ligated rat.

Luo W, Meng Y, Ji HL, Pan CQ, Huang S, Yu CH, Xiao LM, Cui K, Ni SY, Zhang ZS, Li X - PLoS ONE (2012)

Bottom Line: Spironolactone, an aldosterone antagonist, has beneficial effect on hyperdynamic circulation in clinical practice.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.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Southern Medical University, Nanfang Hospital, Guangzhou, China.

ABSTRACT

Objective: Aldosterone, 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.

Methods: Liver 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.

Results: Treatment 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.

Conclusion: Spironolactone 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.

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Spironolactone (Sp) downregulates type I collagen expression and reduces hydroxyproline content in BDL rats.(A) Spironolactone downregulates type I collagen protein expression in the livers of BDL rats, as shown by Western blot analysis (B). Sprionolactone reduces hydroxyproline content in rat livers (C). *p<0.05 compared to the Sham group. #p<0.05 compared to the BDL groups.
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pone-0034230-g002: Spironolactone (Sp) downregulates type I collagen expression and reduces hydroxyproline content in BDL rats.(A) Spironolactone downregulates type I collagen protein expression in the livers of BDL rats, as shown by Western blot analysis (B). Sprionolactone reduces hydroxyproline content in rat livers (C). *p<0.05 compared to the Sham group. #p<0.05 compared to the BDL groups.

Mentions: BDL caused significant histological changes, including a distortion of the normal architecture, expansion of portal tracts with extensive bile-duct proliferation and deposition of collagen (Figure 1A). Spironlactone attenuated liver fibrosis and decreased the collagen deposition significantly compared with the BDL group during two and four weeks. Hepatic hydroxyproline content was increased in BDL-treated rats, while treatment with spironlactone significantly inhibited the secretion of hydroxyproline by 11.2% (two weeks) and 31.3% (four weeks) respectively (Figure 2C). This could be confirmed histologically using Masson's staining (Figure 1B) and the expression of type I collagen by Western blot analysis (Figure 2B). In addition, there was a significant increase in the analyzed biochemical parameters (bilirubin, ALT, and AST) in BDL rats as compared to sham-operated animals (Table 1).


Spironolactone lowers portal hypertension by inhibiting liver fibrosis, ROCK-2 activity and activating NO/PKG pathway in the bile-duct-ligated rat.

Luo W, Meng Y, Ji HL, Pan CQ, Huang S, Yu CH, Xiao LM, Cui K, Ni SY, Zhang ZS, Li X - PLoS ONE (2012)

Spironolactone (Sp) downregulates type I collagen expression and reduces hydroxyproline content in BDL rats.(A) Spironolactone downregulates type I collagen protein expression in the livers of BDL rats, as shown by Western blot analysis (B). Sprionolactone reduces hydroxyproline content in rat livers (C). *p<0.05 compared to the Sham group. #p<0.05 compared to the BDL groups.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3316615&req=5

pone-0034230-g002: Spironolactone (Sp) downregulates type I collagen expression and reduces hydroxyproline content in BDL rats.(A) Spironolactone downregulates type I collagen protein expression in the livers of BDL rats, as shown by Western blot analysis (B). Sprionolactone reduces hydroxyproline content in rat livers (C). *p<0.05 compared to the Sham group. #p<0.05 compared to the BDL groups.
Mentions: BDL caused significant histological changes, including a distortion of the normal architecture, expansion of portal tracts with extensive bile-duct proliferation and deposition of collagen (Figure 1A). Spironlactone attenuated liver fibrosis and decreased the collagen deposition significantly compared with the BDL group during two and four weeks. Hepatic hydroxyproline content was increased in BDL-treated rats, while treatment with spironlactone significantly inhibited the secretion of hydroxyproline by 11.2% (two weeks) and 31.3% (four weeks) respectively (Figure 2C). This could be confirmed histologically using Masson's staining (Figure 1B) and the expression of type I collagen by Western blot analysis (Figure 2B). In addition, there was a significant increase in the analyzed biochemical parameters (bilirubin, ALT, and AST) in BDL rats as compared to sham-operated animals (Table 1).

Bottom Line: Spironolactone, an aldosterone antagonist, has beneficial effect on hyperdynamic circulation in clinical practice.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.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Southern Medical University, Nanfang Hospital, Guangzhou, China.

ABSTRACT

Objective: Aldosterone, 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.

Methods: Liver 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.

Results: Treatment 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.

Conclusion: Spironolactone 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.

Show MeSH
Related in: MedlinePlus