title: Activation of aryl hydrocarbon receptor mediates suppression of hypoxia-inducible factor-dependent erythropoietin expression by indoxyl sulfate.
abstract: Indoxyl sulfate (IS) is a representative uremic toxin that accumulates in the blood of patients with chronic kidney disease (CKD). In addition to the involvement in the progression of CKD, a recent report indicates that IS suppresses hypoxia-inducible factor (HIF)-dependent erythropoietin (EPO) production, suggesting that IS may also contribute to the progression of renal anemia. In this report, we provide evidence that aryl hydrocarbon receptor (AhR) mediates IS-induced suppression of HIF activation and subsequent EPO production. In HepG2 cells, IS at concentrations similar to the blood levels in CKD patients suppressed hypoxia- or cobalt chloride-induced EPO mRNA expression and transcriptional activation of HIF. IS also induced AhR activation, and AhR blockade resulted in abolishment of IS-induced suppression of HIF activation. The HIF transcription factor is a heterodimeric complex composed of HIF-α subunits (HIF-1α and HIF-2α) and AhR nuclear translocator (ARNT). IS suppressed nuclear accumulation of the HIF-α-ARNT complex accompanied by an increase of the AhR-ARNT complex in the nucleus, implying the involvement of interactions among AhR, HIF-α, and ARNT in the suppression mechanism. In rats, oral administration of indole, a metabolic precursor of IS, inhibited bleeding-induced elevation of renal EPO mRNA expression and plasma EPO concentration and strongly induced AhR activation in the liver and renal cortex tissues. Collectively, this study is the first to elucidate the detailed mechanism by which AhR plays an indispensable role in the suppression of HIF activation by IS. Hence, IS-induced activation of AhR may be a potential therapeutic target for treating renal anemia.
authors.affiliation: Safety Research Center, Kureha Corporation, Tokyo, Japan asaih@kureha.co.jp.
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Asai
authors.affiliation: Safety Research Center, Kureha Corporation, Tokyo, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Hirata
authors.affiliation: Safety Research Center, Kureha Corporation, Tokyo, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Hirano
authors.affiliation: Safety Research Center, Kureha Corporation, Tokyo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hirai
authors.affiliation: Safety Research Center, Kureha Corporation, Tokyo, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Seki
authors.affiliation: Safety Research Center, Kureha Corporation, Tokyo, Japan.
authors.forename: Mie
authors.initials: M
authors.lastname: Watanabe-Akanuma
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004921:Erythropoietin / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007200:Indican / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: C554270:EPO protein, human; D051793:Hypoxia-Inducible Factor 1; D018336:Receptors, Aryl Hydrocarbon; D004921:Erythropoietin; D007200:Indican
keywords: aryl hydrocarbon receptor; erythropoietin; hypoxia-inducible factor; indoxyl sulfate; renal anemia