A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model

Muñoz‐Durango, Natalia; Arrese, Marco; Hernández, Alejandra; Jara, Evelyn; Kalergis, Alexis M.; Cabrera, Daniel

doi:10.3389/fimmu.2020.563434

Cited by 18 publications

(15 citation statements)

References 58 publications

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“…Zhang et al (2017) further demonstrated, that the MR directly regulated the estrogen receptor 1 (ERα) in macrophages, which thereby via hepatocyte growth factor (HGF)/Met signalling enhanced lipid accumulation and reduced insulin sensitivity of hepatocytes. These data are in agreement with a study from Munoz‐Durango et al (2020) demonstrating in a NASH model that mice with a myeloid cell‐specific MR inactivation showed reduced hepatic inflammation and lower triglyceride content than controls. While the total number and percentage of liver inflammatory infiltrate cells were similar in both mutants and controls, expression of the co‐stimulatory molecule CD86 by dendritic cells and the CD25 activation marker in CD8 + T cells were significantly reduced in myeloid‐specific mutant livers.…”

Section: Mr In Liver Diseasessupporting

confidence: 93%

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: Mr In Liver Diseasessupporting

confidence: 93%

Mineralocorticoid receptors in non‐alcoholic fatty liver disease

Schreier

Zipprich

Uhlenhaut

et al. 2022

British J Pharmacology

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“…Myeloid cells MR KO has been studied in kidney (31), heart (32,33), and liver disease (34). In a non-alcoholic steatohepatitis model, myeloid cells MR KO decreased fibrosis (34). Similarly, in a progressive glomerulonephritis model, myeloid cells MR KO reduced kidney damage and inflammation (31).…”

Section: Discussionmentioning

confidence: 99%

“…However, smooth muscle cells specific MR KO prevented ischemia-reperfusion induced AKI, via the inhibition of lipid peroxydation (6). Myeloid cells MR KO has been studied in kidney (31), heart (32,33), and liver disease (34). In a non-alcoholic steatohepatitis model, myeloid cells MR KO decreased fibrosis (34).…”

Section: Discussionmentioning

confidence: 99%

Increased severity of chronic kidney disease in response to high potassium intake is dependent on mineralocorticoid receptor activation

Olivier

Arnoux

Ramakrishnan

et al. 2022

Preprint

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Dietary treatment is seminal for management of chronic kidney disease (CKD). The aim of our project was to assess the effects of potassium intake on the progression of CKD. We used 2 mouse CKD models to analyze the effects of potassium intake on CKD : the unilateral ureteral obstruction (UUO) and the POD-ATTAC models. POD-ATTAC mice display a podocyte-specific apoptosis after the administration of a chemical inducer. We also studied the effect of mineralocorticoid receptor (MR) using UUO in kidney tubule-specific MR knockout mice. In both UUO and POD-ATTAC mice, high potassium diet increased interstitial fibrosis. High potassium diet also increased the abundance of the extracellular matrix protein fibronectin and decreased the abundance of the epithelial marker Na+-K+ ATPase. Consistently, POD-ATTAC mice fed with high potassium diet displayed lower glomerular filtration rate. Spironolactone, a MR antagonist, decreased fibrosis induced by high potassium diet in POD-ATTAC mice. However, kidney tubule-specific MR knockout did not improve the fibrotic lesions induced by UUO under normal or high potassium diets. Macrophages from high potassium-fed POD-ATTAC mice displayed higher mRNA levels of the pro-inflammatory chemokine MCP1. This effect was decreased by spironolactone, suggesting a role of MR signaling in myeloid cells in the pro-fibrotic effect of potassium-rich diet. High potassium intake generates more fibrosis leading to decreased kidney function in experimental CKD. MR signaling plays a pivotal role in this potassium-induced fibrosis. The effect of reducing potassium intake on CKD progression should be assessed in future clinical trials.

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“…In a recent study performed in methionine-choline deficient diet (MCD) animals it has been reported that proinflammatory cells are functionally suppressed in the absence of MR. This loss might modulate the adaptive immune response, eventually leading to a reduction in lipid accumulation in the liver ( 27 ).…”

Section: Mechanisms Of Inflammationmentioning

confidence: 99%

Analysis of Common Pathways and Markers From Non-Alcoholic Fatty Liver Disease to Immune-Mediated Diseases

et al. 2021

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Metabolic associated fatty liver disease (MAFLD) is the most prevalent form of liver disease worldwide, accounting for a high liver-related mortality and morbidity with extensive multi-organ involvement. This entity has displaced viral hepatitis as the main cause of severe forms of hepatic diseases, although the onset and transition of MAFLD stages still remains unclear. Nevertheless, innate and adaptive immune responses seem to play an essential role in the establishment and further progression of this disease. The immune system is responsible of safeguard and preserves organs and systems function, and might be altered under different stimuli. Thus, the liver suffers from metabolic and immune changes leading to different injuries and loss of function. It has been stablished that cell-cell crosstalk is a key process in the hepatic homeostasis maintenance. There is mounting evidence suggesting that MAFLD pathogenesis is determined by a complex interaction of environmental, genetic and host factors that leads to a full plethora of outcomes. Therefore, herein we will revisit and discuss the interplay between immune mechanisms and MAFLD, highlighting the potential role of immunological markers in an attempt to clarify its relationship.

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A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model

Cited by 18 publications

References 58 publications

Mineralocorticoid receptors in non‐alcoholic fatty liver disease

Mineralocorticoid receptors in non‐alcoholic fatty liver disease

Increased severity of chronic kidney disease in response to high potassium intake is dependent on mineralocorticoid receptor activation

Analysis of Common Pathways and Markers From Non-Alcoholic Fatty Liver Disease to Immune-Mediated Diseases

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