The effects of the selective mineralocorticoid receptor antagonist eplerenone on hepatic fibrosis induced by bile duct ligation in rat

Abstract

Abstract. The aim of this study was to examine the effects of eplerenone on hepatic fibrosis induced by bile duct ligation (BDL) in rat. Low-(1.0 mg/kg body weight, BW) and high-(4.0 mg/kg BW) dose eplerenone was administered orally for 21 days immediately following BDL. Fibrosis was assessed by measuring the fibrotic area after Sirius red staining. Immunostaining for ·-smooth muscle actin (SMA), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) was also carried out. Gene expression levels of procollagen-I, transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinases-1 (TIMP-1) and matrix metalloproteinase-13 (MMP-13) in the liver were examined by real-time reverse transcriptase polymerase chain reaction. Plasma angiotensin II (ATII) concentration was measured via radioimmunoassay. The area of hepatic fibrosis and ·-SMA positivity in the high-dose group was significantly decreased compared with that in the BDL group, but not in the low-dose group. 8-OHdG-positive cells in the low-and high-dose groups were significantly decreased compared with those in the BDL group. Immunostaining of 4-HNE in the high-dose group was significantly lower compared with that in the BDL group. Furthermore, TIMP-1 mRNA levels in the low-and high-dose groups were lower than that in the BDL group. The expression of TGF-ß1, CTGF, procollagen-1 and MMP-13 showed no differences. Plasma ATII concentration in the high-dose group was significantly decreased. Eplerenone attenuated the development of BDL-induced hepatic fibrosis by reducing oxidative stress, suppressing activated hepatic stellate cells and decreasing plasma ATII levels. Eplerenone may prove useful as an alternative treatment for antifibrosis therapy. IntroductionAngiotensin II (ATII) and aldosterone are the main effector peptides of the renin-angiotensin-aldosterone system (RAAS) and are known to be important mediators of hepatic fibrosis and portal hypertension (1-5). ATII and aldosterone stimulate the proliferation of hepatic stellate cells (HSC) and collagen synthesis, and are involved in the generation of reactive oxygen species (ROS) both in vitro and in vivo (6-8). ATII type 1 receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) have been reported to prevent the development of hepatic fibrosis in numerous animal (6-12) and human (13-15) studies. However, only a few studies examining the antifibrotic effects of aldosterone blockers have been reported to date. The results arising from these studies have proven to be controversial (1,2,5). Fujisawa et al (5) reported that spironolactone prevented pig serum-induced hepatic fibrosis in rats, while Oberti et al (2) showed that spironolactone did not produce any anti-fibrotic effects during bile duct ligation (BDL)-induced hepatic fibrosis.The novel aldosterone blocker eplerenone has been shown to exhibit a high specificity for mineralocorticoid receptors (16,17). While the efficacy and safety of eplerenone in the treatment of hype...

The circadian rhythm of bladder clock genes in the spontaneously hypersensitive rat

“…Rats were euthanized by isoflurane/CO 2 euthanasia without fasting. RNA in the bladder was measured by polymerase chain reaction (PCR) as previously reported [20]. In brief, bladder samples were homogenized and total RNA was extracted using an RNeasy Mini Kit (Qiagen, Hilden, Germany).…”

Hepatoprotective Effect of Eplerenone, A Selective Mineralocorticoid Receptor Antagonist, Against Thioacetamide Induced Liver Injury in Rats

“…Activation of mineralocorticoid receptor by aldosterone was documented to increases oxidative stress through increasing reactive oxygen species (ROS) as well as reducing ROS scavenging capacity of the cells [20,36,37] via activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme [38].…”