scholarly journals Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor

2020 ◽  
Vol 21 (10) ◽  
pp. 3486 ◽  
Author(s):  
Wen-Chih Liu ◽  
Jia-Fwu Shyu ◽  
Paik Seong Lim ◽  
Te-Chao Fang ◽  
Chien-Lin Lu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Critical Role ◽  
Osteoclast Differentiation ◽  
Indoxyl Sulfate ◽  
Raw 264.7 Cells ◽  
High Dose ◽  
Activated T Cells ◽  
Aryl Hydrocarbon

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients.

scholarly journals Toxic Effects of Indoxyl Sulfate on Osteoclastogenesis and Osteoblastogenesis

2021 ◽  
Vol 22 (20) ◽  
pp. 11265
Author(s):  
Jia-Fwu Shyu ◽  
Wen-Chih Liu ◽  
Cai-Mei Zheng ◽  
Te-Chao Fang ◽  
Yi-Chou Hou ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dynamic Balance ◽  
Osteoclast Differentiation ◽  
Uremic Toxins ◽  
Indoxyl Sulfate ◽  
Toxic Effects ◽  
High Dose ◽  
Activated T Cells ◽  
Aryl Hydrocarbon ◽  
Bone Damage

Uremic toxins, such as indoxyl sulfate (IS) and kynurenine, accumulate in the blood in the event of kidney failure and contribute to further bone damage. To maintain the homeostasis of the skeletal system, bone remodeling is a persistent process of bone formation and bone resorption that depends on a dynamic balance of osteoblasts and osteoclasts. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the toxic effects of uremic toxins. IS is an endogenous AhR ligand and is metabolized from tryptophan. In osteoclastogenesis, IS affects the expression of the osteoclast precursor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) through AhR signaling. It is possible to increase osteoclast differentiation with short-term and low-dose IS exposure and to decrease differentiation with long-term and/or high-dose IS exposure. Coincidentally, during osteoblastogenesis, through the AhR signaling pathway, IS inhibits the phosphorylation of ERK, and p38 reduces the expression of the transcription factor 2 (Runx2), disturbing osteoblastogenesis. The AhR antagonist resveratrol has a protective effect on the IS/AhR pathway. Therefore, it is necessary to understand the multifaceted role of AhR in CKD, as knowledge of these transcription signals could provide a safe and effective method to prevent and treat CKD mineral bone disease.

scholarly journals Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation

2016 ◽  
Vol 23 (8) ◽  
pp. 960-975 ◽  
Author(s):  
Shunsuke Ito ◽  
Mizuko Osaka ◽  
Takeo Edamatsu ◽  
Yoshiharu Itoh ◽  
Masayuki Yoshida
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Crucial Role ◽  
Vascular Inflammation ◽  
Indoxyl Sulfate ◽  
Aryl Hydrocarbon

scholarly journals Role of Resveratrol on Indoxyl Sulfate-Induced Endothelial Hyperpermeability via Aryl Hydrocarbon Receptor (AHR)/Src-Dependent Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Eskedar Getachew Assefa ◽  
Qiaoqiao Yan ◽  
Siameregn Berhe Gezahegn ◽  
Maibouge Tanko Mahamane Salissou ◽  
Shuiqing He ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Src Kinase ◽  
Endothelial Permeability ◽  
High Serum ◽  
Indoxyl Sulfate ◽  
Dietary Polyphenols ◽  
Aryl Hydrocarbon ◽  
Dependent Pathway ◽  
Endothelial Hyperpermeability

Resveratrol (RES), a dietary polyphenol compound, has been shown to possess health benefits due to its anti-inflammatory, antioxidative, and antiatherosclerosis properties. Tryptophan metabolite-derived indoxyl sulfate (IS) is identified as one of the uremic toxins and physiological endogenous ligand/activator of aryl hydrocarbon receptor (AHR), associated with atherosclerosis in chronic kidney disease (CKD) patients. Studies have shown that a high serum level of IS causes deleterious effects on health primarily by inducing oxidative stress and endothelial dysfunction. However, the precise mechanisms are still unclear. Here, we investigated the underlying mechanism of IS effect on endothelial permeability and the role of RES on IS-induced endothelial hyperpermeability via the AHR/Src-dependent pathway. Bovine aorta endothelial cells (BAECs) were cultured and incubated with IS in the presence or absence of RES, and transendothelial electrical resistance (TEER) and permeability of cells were measured. Alongside, AHR, Src kinase, and Vascular Endothelial Cadherin (VE-Cadherin) activation were examined. Our data showed that IS reduced TEER of cells resulting in increased permeability. VE-Cadherin, a vital regulator of endothelial permeability, was also significantly activated in response to IS, which appeared to be associated with changes of endothelial permeability and AHR/Src kinase. Interestingly, in this setting, RES reversed the effect of IS and inhibited the increased activation of Src induced by IS-activated AHR and modulated VE-Cadherin and permeability. CH223191, an inhibitor of AHR, significantly inhibits IS-induced endothelial hyperpermeability. Further analysis with treatment of PP2, an inhibitor of Src abolishing Src activation, suggests downstream factors. All our data indicated that IS upregulated the AHR/Src kinase pathway, and increased endothelial permeability and phosphorylation of VE-Cadherin may be represented and provide new strategies for addressing protective properties of RES against Src kinase involved in AHR-mediated endothelial hyperpermeability. The findings may be crucial for managing diseases in which endothelial permeability is compromised, and the dietary polyphenols are involved.

Aryl hydrocarbon receptor protects against viridans streptococci infection by activation of immune system through IL-17RA signaling

2015 ◽  
Vol 3 (2) ◽  
pp. 400-410
Author(s):  
Guowei Liang ◽  
Keyword(s):  
Immune Responses ◽  
Aryl Hydrocarbon Receptor ◽  
Bacterial Infections ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Microbial Infection ◽  
Viridans Streptococci ◽  
Coagulase Negative Staphylococci ◽  
Aryl Hydrocarbon

The majority of bacterial infections during neutropenia following high-dose chemotherapy or stem cell transplantation are caused by coagulase-negative staphylococci, a large number are due to viridans streptococci. Despite considerable progress in the understanding of the AhR-mediated regulation of immune responses, the role of AhR in bacterial infections has not been clearly demonstrated. In the study presented here, we sought to determine whether the aryl hydrocarbon receptor (AhR) would protect mice from infection with viridans streptococci. AhR enhances the inflammatory response to viridans streptococci stimuli. Specifically, neutrophil numbers and levels of inflammatory cytokines are often increased in mice treated with viridans streptococci. Furthermore, AhR activation through the IL-17RA is required for protection against viridans streptococcal infection. Taken together, we concluded that AhR plays an important role in optimal innate immunoprotection against microbial infection through the down-regulation of immune response.

scholarly journals Trajectory Shifts in Interdisciplinary Research of the Aryl Hydrocarbon Receptor—A Personal Perspective on Thymus and Skin

2021 ◽  
Vol 22 (4) ◽  
pp. 1844
Author(s):  
Charlotte Esser
Keyword(s):  
Transcription Factor ◽  
Immune System ◽  
Environmental Pollution ◽  
Aryl Hydrocarbon Receptor ◽  
Interdisciplinary Research ◽  
Adaptive Response ◽  
Personal Perspective ◽  
Aryl Hydrocarbon

Identifying historical trajectories is a useful exercise in research, as it helps clarify important, perhaps even “paradigmatic”, shifts in thinking and moving forward in science. In this review, the development of research regarding the role of the transcription factor “aryl hydrocarbon receptor” (AHR) as a mediator of the toxicity of environmental pollution towards a link between the environment and a healthy adaptive response of the immune system and the skin is discussed. From this fascinating development, the opportunities for targeting the AHR in the therapy of many diseases become clear.

scholarly journals SP398CRUCIAL ROLE OF ARYL HYDROCARBON RECEPTOR IN INDOXYL Sulfate-INDUCED VASCULAR INFLAMMATION

2015 ◽  
Vol 30 (suppl_3) ◽  
pp. iii510-iii511
Author(s):  
Shunsuke Ito ◽  
Mizuko Osaka ◽  
Naoki Sawada ◽  
Takeo Edamatsu ◽  
Yoshiharu Itoh ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Vascular Inflammation ◽  
Indoxyl Sulfate ◽  
Aryl Hydrocarbon

scholarly journals The Aryl Hydrocarbon Receptor Relays Metabolic Signals to Promote Cellular Regeneration

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Fanny L. Casado
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Transcription Factor ◽  
Regenerative Medicine ◽  
Aryl Hydrocarbon Receptor ◽  
Signaling Pathways ◽  
Metabolic Efficiency ◽  
Aryl Hydrocarbon ◽  
Cellular Regeneration

While sensing the cell environment, the aryl hydrocarbon receptor (AHR) interacts with different pathways involved in cellular homeostasis. This review summarizes evidence suggesting that cellular regeneration in the context of aging and diseases can be modulated by AHR signaling on stem cells. New insights connect orphaned observations into AHR interactions with critical signaling pathways such as WNT to propose a role of this ligand-activated transcription factor in the modulation of cellular regeneration by altering pathways that nurture cellular expansion such as changes in the metabolic efficiency rather than by directly altering cell cycling, proliferation, or cell death. Targeting the AHR to promote regeneration might prove to be a useful strategy to avoid unbalanced disruptions of homeostasis that may promote disease and also provide biological rationale for potential regenerative medicine approaches.

scholarly journals Metabolic profiling during malaria reveals the role of the aryl hydrocarbon receptor in regulating kidney injury

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Michelle M Lissner ◽  
Katherine Cumnock ◽  
Nicole M Davis ◽  
José G Vilches-Moure ◽  
Priyanka Basak ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Metabolic Response ◽  
Acute Infection ◽  
Critical Role ◽  
Kidney Injury ◽  
High Plasma ◽  
Metabolic Reprogramming ◽  
Aryl Hydrocarbon ◽  
Specific Effects

Systemic metabolic reprogramming induced by infection exerts profound, pathogen-specific effects on infection outcome. Here, we detail the host immune and metabolic response during sickness and recovery in a mouse model of malaria. We describe extensive alterations in metabolism during acute infection, and identify increases in host-derived metabolites that signal through the aryl hydrocarbon receptor (AHR), a transcription factor with immunomodulatory functions. We find that Ahr-/- mice are more susceptible to malaria and develop high plasma heme and acute kidney injury. This phenotype is dependent on AHR in Tek-expressing radioresistant cells. Our findings identify a role for AHR in limiting tissue damage during malaria. Furthermore, this work demonstrates the critical role of host metabolism in surviving infection.

scholarly journals The aryl hydrocarbon receptor and the gut–brain axis

2021 ◽  
Author(s):  
Andreia Barroso ◽  
João Vitor Mahler ◽  
Pedro Henrique Fonseca-Castro ◽  
Francisco J. Quintana
Keyword(s):  
Transcription Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Therapeutic Target ◽  
Potential Value ◽  
Aryl Hydrocarbon ◽  
Immune Mediated ◽  
Health And Disease

AbstractThe aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor initially identified as the receptor for dioxin. Almost half a century after its discovery, AHR is now recognized as a receptor for multiple physiological ligands, with important roles in health and disease. In this review, we discuss the role of AHR in the gut–brain axis and its potential value as a therapeutic target for immune-mediated diseases.

Sign in / Sign up

Export Citation Format

Share Document