Selective aldosterone blocker ameliorates the progression of non-alcoholic steatohepatitis in rats

Abstract

Abstract. Although non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma (HCC), no effective therapeutic modalities have been fully established yet. Recent studies have shown that the reninangiotensin-aldosterone-system plays an important role in NASH. The aim of our current study was to elucidate the effects of aldosterone (Ald) inhibition on the progression of NASH. In the choline-deficient L-amino acid-defined dietinduced rat NASH model, the effects of a clinically used selective Ald blocker (SAB) were elucidated in conjunction with the activated hepatic stellate cells (HSC) and neovascularization, which are both known to play important roles in liver fibrosis development and hepatocarcinogenesis, respectively. Liver fibrosis development and the glutathione-S-transferase placental form-positive pre-neoplastic lesions were both markedly attenuated by SAB along with the suppression of the activated HSC and neovascularization. SAB inhibited the hepatic expression of transforming growth factor-ß 1 and also that of the vascular endothelial growth factor. Our in vitro study showed that SAB also inhibited the Ald-induced HSC proliferation and in vitro angiogenesis in a dose-dependent manner. These results indicated that Ald plays a pivotal role in the progression of NASH. Considering that SAB is already widely used in clinical practice, this drug could represent a potential new strategy against NASH in the future.

Relationship Between Plasma Aldosterone Concentrations and Non-Alcoholic Fatty Liver Disease Diagnosis in Patients with Hypertension: A Retrospective Cohort Study

“…Together, these treatment results indicated that aldosterone plays a pivotal role in the progression of NAFLD. 27 In subgroup analysis, our study found that the risk of NAFLD was associated with a higher PAC in hypertensive patients without diabetes than in those with diabetes. The reason underlying the association was the number of diabetes patients who accepted antidiabetic agents, including metformin, insulin, pioglitazone, glucagon-like peptide-1 agonists, sodium-glucose co-transporter-2, and dipeptidyl peptidase-4 inhibitors, which had a beneficial effect on the prevention of NAFLD.…”

“… 26 A selective aldosterone blocker (SAB) has been shown to attenuate fibrogenesis and suppress activated hepatic stellate cells in other studies. 27 However, one study suggests that aldosterone excess may not be correlated with the development of fatty liver disease in a mouse model fed a high-fat diet. 28 Nevertheless, there is a need for further investigation into the association between high plasma aldosterone concentrations (PAC) and NAFLD in hypertensive patients, given the controversial findings.…”

Non-Alcoholic Fatty Liver Disease and Hypokalemia in Primary Aldosteronism Among Chinese Population

“…Additionally, a negative correlation between plasma aldosterone and HDL cholesterol levels was reported in essential hypertensive patients with obesity and insulin resistance early on that was not found in later studies (18,23). After the correction of excess aldosterone, either by surgery in patients with aldosteronoma or medication in those with hyperplasia, significant improvements in the metabolic parameters were observed (24)(25)(26). Consistent with this finding, our study also showed that metabolic disorders, especially NAFLD, diabetes and dyslipidemia, were more prevalent in PA patients than in non-PA patients.…”

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

“…Other major effects of the hormone include the induction of proinflammatory activity, which leads to the progressive fibrotic damage of the target organs, heart and kidney. Blocking the aldosterone receptor, therefore, represents an important pharmacological strategy to avoid the clinical conditions arising from NASH [ 98 , 99 ] and CKD [ 100 , 101 , 102 ]. Apararenone (MT-3995) [ 103 ] is a nonsteroidal antimineralocorticoid which is under development for the treatment of diabetic nephropathies and NASH ( Table 1 ).…”