Aryl Hydrocarbon Receptor Activation in Chronic Kidney Disease: Role of Uremic Toxins.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in the expression of xenobiotic-metabolizing enzymes, inflammatory cytokines and adhesion molecules. Uremic toxins such as indoxyl sulfate and indole acetic acid are derived from tryptophan fermentation by gut microbiota; they accumulate in patients with chronic kidney disease (CKD) on haemodialysis and have recently emerged as potent ligands of AhR. Therefore, AhR can serve as a mediator in inflammation and cardiovascular diseases in these patients. This review discusses current data that support a link between AhR activation and uremic toxins from gut microbiota in CKD.

Brito JS ，Borges NA ，Esgalhado M ，Magliano DC ，Soulage CO ，Mafra D ... -  《-》

The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease.

Sallée M ，Dou L ，Cerini C ，Poitevin S ，Brunet P ，Burtey S ... -  《Toxins》

Aryl Hydrocarbon Receptor and Uremic Toxins from the Gut Microbiota in Chronic Kidney Disease Patients: Is There a Relationship between Them?

Brito JS ，Borges NA ，Anjos JSD ，Nakao LS ，Stockler-Pinto MB ，Paiva BR ，Cardoso-Weide LC ，Cardozo LFMF ，Mafra D ... -  《-》

Tryptophan Metabolites Regulate Neuropentraxin 1 Expression in Endothelial Cells.

Vial R ，Poitevin S ，McKay N ，Burtey S ，Cerini C ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Indoxyl glucuronide, a protein-bound uremic toxin, inhibits hypoxia-inducible factor‒dependent erythropoietin expression through activation of aryl hydrocarbon receptor.

Renal anemia is common among chronic kidney disease (CKD) patients, and is mainly caused by inadequate erythropoietin (EPO) production from kidneys due to dysfunction of intracellular hypoxia-inducible factor (HIF) signaling in renal EPO-producing cells. We have previously shown that indoxyl sulfate (IS), a representative protein-bound uremic toxin accumulated in the blood of CKD patients, inhibits hypoxia-induced HIF activation and subsequent EPO production through activation of aryl hydrocarbon receptor (AHR). In this study, we further investigated the effects of other protein-bound uremic toxins on HIF-dependent EPO expression using EPO-producing HepG2 cells. We found that indoxyl glucuronide (IG) and IS, but not p-cresyl sulfate, phenyl sulfate, 3-indoleacetic acid or hippuric acid, inhibited hypoxia mimetic cobalt chloride-induced EPO mRNA expression. Furthermore, IG at concentrations similar to the blood levels in CKD patients inhibited the transcriptional activation of HIF induced by both cobalt chloride treatment and hypoxic culture. IG also induced CYP1A1 mRNA expression and nuclear translocation of AHR protein, indicating that IG activates AHR signaling. Blockade of AHR by a pharmacological antagonist CH-223191 abolished the IG-induced inhibition of HIF activation. Collectively, this study is the first to elucidate the biological effects of IG to inhibit HIF-dependent EPO production through activation of AHR. Our data suggests that not only IS but also IG contributes to the impairment of HIF signaling in renal anemia.

Asai H ，Hirata J ，Watanabe-Akanuma M 《-》