The selective mineralocorticoid receptor antagonist eplerenone prevents decompensation of the liver in cirrhosis

Schreier, Barbara; Wolf, Anja; Hammer, Stefanie; Pohl, Sabine; Mildenberger, Sigrid; Rabe, Sindy; Gekle, Michael; Zipprich, Alexander

doi:10.1111/bph.14341

Cited by 16 publications

(12 citation statements)

References 49 publications

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“…It is possible that there are cell type‐specific effects on MR expression, as in mice fed with a choline‐deficient and amino‐acid defined (CDAA) diet, an increase in MR mRNA was observed in HSCs but a reduction in hepatocytes (Pizarro et al, 2015). We also observed a reduction of MR mRNA content in freshly isolated hepatocytes from rats with decompensated liver cirrhosis (Schreier et al, 2018). If this reduced mRNA content is due to reduced transcription or enhanced mRNA degradation is still under investigation, as well as the underlying molecular pathways.…”

Section: Function Of the Mineralocorticoid Receptor And Aldosterone I...supporting

confidence: 55%

“…Progression of liver dysfunction depends on the crosstalk of the different cell types within the liver but, while there is evidence that inhibition of the MR is beneficial for liver function (see below), little is known about the cellular mechanisms leading to this effect. In healthy rat livers, the main cell type expressing MRs, at mRNA and protein levels, is the hepatocytes (Schreier et al, 2018), although there are also MRs detectable in LSECs and Kupffer cells (Pizarro et al, 2015). At the moment, it is not clear if rat HSCs also express MRs, as we could detect the appropriate mRNA but not the protein (Schreier et al, 2018).…”

Section: Function Of the Mineralocorticoid Receptor And Aldosterone I...mentioning

confidence: 99%

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Mineralocorticoid receptors in non‐alcoholic fatty liver disease

Schreier

Zipprich

Uhlenhaut

et al. 2022

British J Pharmacology

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Liver diseases are the fourth common death in Europe responsible for about 2 million death per year worldwide. Among the known detrimental causes for liver dysfunction are virus infections, intoxications and obesity. The mineralocorticoid receptor (MR) is a ligand‐dependent transcription factor activated by aldosterone or glucocorticoids but also by pathological milieu factors. Canonical actions of the MR take place in epithelial cells of kidney, colon and sweat glands and contribute to sodium reabsorption, potassium secretion and extracellular volume homeostasis. The non‐canonical functions can be initiated by inflammation or an altered micro‐milieu leading to fibrosis, hypertrophy and remodelling in various tissues. This narrative review summarizes the evidence regarding the role of MR in portal hypertension, non‐alcoholic fatty liver disease, liver fibrosis and cirrhosis, demonstrating that inhibition of the MR in vivo seems to be beneficial for liver function and not just for volume regulation. Unfortunately, the underlying molecular mechanisms are still not completely understood. LINKED ARTICLES This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone‐Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc

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Section: Function Of the Mineralocorticoid Receptor And Aldosterone I...supporting

confidence: 55%

Section: Function Of the Mineralocorticoid Receptor And Aldosterone I...mentioning

confidence: 99%

Mineralocorticoid receptors in non‐alcoholic fatty liver disease

Schreier

Zipprich

Uhlenhaut

et al. 2022

British J Pharmacology

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“…In recent years, many studies have found that NR3C2 serves as a tumor suppressor in many cancers, including hepatocellular carcinoma ( Nie et al, 2015 ; Yang et al, 2019 ). Although NR3C2 status in ACLF has not been explored, MR mRNA and protein expression were reduced in the hepatocytes of patients with cirrhosis and ascites ( Schreier et al, 2018 ). In HBV-ACLF patients, we found that NR3C2 expression was significantly lower among both those with a poor prognosis and those with ACLF-3 grade disease.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Potential miRNA–mRNA Regulatory Network Associated With the Prognosis of HBV-ACLF

Xie

Zhang

et al. 2021

Front. Mol. Biosci.

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BackgroundHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening disease with a high mortality rate; the systemic inflammatory response plays a vital role in disease progression. We aimed to determine if a miRNA–mRNA co-regulatory network exists in the peripheral blood mononuclear cells (PBMCs) of HBV-ACLF patients, which might be important for prognosis.MethodsIn patients with HBV-ACLF meeting COSSH-ACLF criteria, age, liver cirrhosis and INR were independent risk factors for 28-day and 90-day poor prognosis. COSSH-ACLFs was a superior prognostic model. mir-6840-3p-JADE2 may promote the progression of ACLF and lead to poor prognosis. Meanwhile, mir-6840-3p and mir-6861-3p can be used as markers of short-term poor prognosis. Finally, ALSS treatment is not only the blood material exchange of patients, but also changes part of the immune state of patients. Among them, cytokine cytokine receptor interaction may play an important role in determining the therapeutic effect.MethodsTranscriptome-wide microRNA (miRNA) and mRNA microarrays were used to define the miRNA and mRNA expression profiles of the PBMCs of HBV-ACLF patients in a discovery cohort. The targets of the miRNAs were predicted. We built a miRNA-mRNA regulatory network through bioinformatics analysis, and used quantitative real-time polymerase chain reaction (qRT-PCR) to assess the importance of candidate miRNAs and mRNAs. We also assessed the direct and transcriptional regulatory effects of miRNAs on target mRNAs using a dual-luciferase reporter assay.ResultsThe miRNA/mRNA PBMC expression profiles of the discovery cohort, of whom eight survived and eight died, revealed a prognostic interactive network involving 38 miRNAs and 313 mRNAs; this was constructed by identifying the target genes of the miRNAs. We validated the expression data in another cohort, of whom 43 survived and 35 died; miR-6840-3p, miR-6861-3p, JADE2, and NR3C2 were of particular interest. The levels of miR-6840-3p and miR-6861-3p were significantly increased in the PBMCs of the patients who died, and thus predicted prognosis (areas under the curve values = 0.665 and 0.700, respectively). The dual-luciferase reporter assay indicated that miR-6840-3p directly targeted JADE2.ConclusionWe identified a prognostic miRNA-mRNA co-regulatory network in the PBMCs of HBV-ACLF patients. miR-6840-3p-JADE2 is a potential miRNA–mRNA pair contributing to a poor prognosis.

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“…Stimulation of mineralocorticoid receptor expression in the liver against the background of IRP causes pro-inflammatory and profibrotic effects. It was discovered that an increase in the mRNA level in the liver significantly correlates with the expression of pro-inflammatory and profibrotic genes, while use of a specific mineralocorticoid receptor blocker, eplerenone, weakens these effects [15,16]. Our study has demonstrated that in rats, characterized by the low resistance to hypoxia, the vectors of fluctuations in the corticosterone concentrations, as well as in the numbers of its target receptors, were multidirectional on day 3 after the IRP: an increase in the corticosteroid level was accompanied by a reduction in the mineralocorticoid content.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant Activity Of Rat Liver With A Low Resistance To Hypoxia After Systemic Ischemia Reperfusion

et al. 2021

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Objective — To assess the antioxidant activity of rat liver after systemic ischemia reperfusion (IRP). Material and Methods — The study was conducted on 70 male rats. For all animals of the treatment group (n=35) under ether anesthesia, we were stopping stopping systemic circulation for five minutes. After that, the animals were given an external cardiac massage and artificial lung ventilation. We did not perform circulatory arrest after ether anesthesia in animals of the control group (n=35). In all animals, we were measuring the levels of serum hormones (corticosterone, aldosterone), the content of glucocorticoid and mineralocorticoid receptors in liver homogenates, and the activity of enzymes of the antioxidant system (superoxide dismutase and catalase). We were making control measurements on days 1, 3, 5, 7, 14, 21, and 35 after the simulated IRP. Results — On day 1 after simulation of IRP development, the levels of cortisol and aldosterone in the serum of treatment group rats were significantly higher, by 14.3% and 33.5%, respectively, compared with the control group. In response to stress (IRP), we observed the highest concentration of cortisol in the blood of treatment group rats on day 3 (p=0.0002), which decreased afterwards. On day 1 after IRP, there was a reduction in the activity of superoxide dismutase and catalase in treatment group rats, by 50.3% and by 29%, respectively (p<0.0001). The lowest antioxidant activity in the rat liver after IRP was observed on days 3-7. Conclusion — Systemic IRP is associated with pronounced changes in the dynamics of corticosteroid receptors in the liver, which leads to a reduction in the activity of key antioxidant enzymes.

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The selective mineralocorticoid receptor antagonist eplerenone prevents decompensation of the liver in cirrhosis

Cited by 16 publications

References 49 publications

Mineralocorticoid receptors in non‐alcoholic fatty liver disease

Mineralocorticoid receptors in non‐alcoholic fatty liver disease

Identification of a Potential miRNA–mRNA Regulatory Network Associated With the Prognosis of HBV-ACLF

Antioxidant Activity Of Rat Liver With A Low Resistance To Hypoxia After Systemic Ischemia Reperfusion

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