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

• Published in: Biochemical and biophysical research communications Vol. 504; no. 2; pp. 538 - 544
• Main Authors: Asai, Hirobumi, Hirata, Junya, Watanabe-Akanuma, Mie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.10.2018
• Subjects: 60 APPLIED LIFE SCIENCES; ANEMIAS; Aryl hydrocarbon receptor; BLOOD; COBALT CHLORIDES; ERYTHROPOIETIN; HIPPURIC ACID; Hypoxia-inducible factor; Indoxyl glucuronide; Indoxyl sulfate; KIDNEYS; MESSENGER-RNA; TOXINS; Hypoxia-inducible factor; Aryl hydrocarbon receptor; Indoxyl glucuronide; Erythropoietin; Indoxyl sulfate
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.09.018

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. •Indoxyl glucuronide (IG) is a protein-bound uremic toxin.•IG inhibited hypoxia-induced HIF transcriptional activation and EPO expression.•IG activated aryl hydrocarbon receptor (AHR) signaling pathway.•The AHR antagonist abolished the inhibitory effect of IG on HIF activation.•IG-induced activation of AHR may contribute to the progression of renal anemia.