Activation of aryl hydrocarbon receptor mediates suppression of hypoxia-inducible factor-dependent erythropoietin expression by indoxyl sulfate
Activation of aryl hydrocarbon receptor mediates suppression of hypoxia-inducible factor-dependent erythropoietin expression by indoxyl sulfate
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DOI：
10.1152/ajpcell.00172.2015
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发表时间：
2016-01-15
影响因子：
5.5
通讯作者：
Watanabe-Akanuma, Mie
中科院分区：
文献类型：
--
作者：
Asai, Hirobumi;Hirata, Junya;Watanabe-Akanuma, Mie
硫酸吲哚酚（IS）是一种代表性的尿毒症毒素，在慢性肾脏疾病（CKD）患者的血液中蓄积。除了参与CKD的进展外，最近的一份报告表明IS抑制缺氧诱导因子（HIF）依赖性促红细胞生成素（EPO）的产生，这表明IS也可能有助于肾性贫血的进展。在本报告中，我们提供了证据表明芳烃受体（AhR）介导IS诱导的对HIF激活和随后EPO产生的抑制。在HepG 2细胞中，浓度与CKD患者血液水平相似的IS抑制缺氧或氯化钴诱导的EPO mRNA表达和HIF的转录激活。IS也诱导AhR激活，AhR阻断导致IS诱导的HIF激活抑制的废除。HIF转录因子是由HIF-α亚基（HIF-1 α和HIF-2 α）和AhR核转运子（ARNT）组成的异二聚体复合物。IS抑制HIF-α-ARNT复合物的核积累，伴随着细胞核中AhR-ARNT复合物的增加，这意味着抑制机制中涉及AhR、HIF-α和ARNT之间的相互作用。在大鼠中，口服吲哚，IS的代谢前体，抑制出血诱导的肾EPO mRNA表达和血浆EPO浓度的升高，并强烈诱导肝和肾皮质组织中AhR的激活。总的来说，这项研究是第一个阐明详细的机制，AhR发挥了不可或缺的作用，抑制HIF激活IS。因此，IS诱导的AhR激活可能是治疗肾性贫血的潜在治疗靶点。
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-alpha subunits (HIF-1 alpha and HIF-2 alpha) and AhR nuclear translocator (ARNT). IS suppressed nuclear accumulation of the HIF-alpha-ARNT complex accompanied by an increase of the AhR-ARNT complex in the nucleus, implying the involvement of interactions among AhR, HIF-alpha, 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.