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.

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The protein-bound polysaccharide isolated from basidiomycetes (PSK), a biological response modifier, has been used as immunotherapeutic agent for the treatment of cancers. It has been demonstrated previously that PSK activates various types of immune cells in vitro, and orally administrated PSK activates anti-tumor CD4+ T cell response in mesenteric lymph nodes (MLNs). The detailed mechanism of action of PSK, however, has not been elucidated yet. The objective of the present study was to clarify the molecular mechanism of immunopotentiating effects of PSK using primary culture of the MLN CD4+ T cells. T cell receptor (TCR) stimulation-induced interleukin-2 production from MLN CD4+ T cells was significantly augmented by PSK in a concentration-dependent manner, and the augmentation was reflected at mRNA level. Furthermore, PSK augmented transcriptional activities of nuclear factor of activated T cells and activator protein 1, and phosphorylation of extracellular signal-regulated kinase 1/2 and linker for activation of T cells induced by TCR stimulation, whereas PSK had no influences without TCR stimulation. Collectively, the results indicate that PSK augments activation of MLN CD4+ T cells, probably by modulating the TCR signaling, and provide important knowledge for the elucidation of the true target molecule(s) of PSK.