In the last decade, extensive attention has been paid to the uremic toxin indoxyl sulphate (IS) as an inducer of cardiac fibroblast (cFib) activation and cardiac fibrosis in chronic kidney disease. At cellular level, IS engages aryl hydrocarbon receptor (AhR) and regulates many biological functions. We analysed how AhR inhibition by CH‐223191 (CH) and overexpression of non‐functional (dominant negative, DN) nuclear factor‐erythroid‐2‐related factor 2 (NRF2), a transcription factor recruited by AhR, modulate the response of neonatal mouse (nm) cFib to IS. We also evaluated nm‐cardiomyocytes after incubation with the conditioned medium (CM) of IS±CH‐treated nm‐cFib. IS induced activation, collagen synthesis, TLR4 and–downstream–MCP‐1, and the genes encoding angiotensinogen, angiotensin‐converting enzyme, angiotensin type 1 receptor (AT1r) and neprilysin (Nepr) in nm‐cFib. CH antagonized IS‐initiated nm‐cFib activation, but did not affect or even magnified the other features. IS promoted NRF2 nuclear translocation and expression the NRF2 target Nqo1. Both pre‐incubation with CH and transfection of DN‐NRF2 resulted in loss of NRF2 nuclear localization. Moreover, DN‐NRF2 overexpression led to greater TLR4 and MCP‐1 levels following exposure to IS. The CM of IS‐primed nm‐cFib and to a larger extent the CM of IS+CH‐treated nm‐cFib upregulated AT1r, Nepr and TNFα and myostatin genes in nm‐cardiomyocytes. Hence, IS triggers pro‐inflammatory activation of nm‐cFib partly via AhR, and AhR‐NRF2 counteract it. Strategies other than AhR inhibition are needed to target IS detrimental actions on cardiac cells.

中文翻译：

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硫酸吲哚酚引发的心脏成纤维细胞活化受芳基烃受体和核因子-红细胞-2相关因子2调节

在过去的十年中，尿毒症毒素硫酸吲哚酚 (IS) 作为慢性肾脏疾病中心脏成纤维细胞 (cFib) 激活和心脏纤维化的诱导剂受到了广泛关注。在细胞水平上，IS 与芳烃受体 (AhR) 结合并调节许多生物功能。我们分析了 CH-223191 (CH) 抑制 AhR 和非功能性（显性失活，DN）核因子红细胞 2 相关因子 2 (NRF2)（AhR 招募的转录因子）的过度表达如何调节新生儿的反应小鼠 (nm) cFib 至 IS。我们还评估了与 IS±CH 处理的 nm-cFib 的条件培养基 (CM) 一起孵育后的 nm-心肌细胞。 IS 诱导激活、胶原蛋白合成、TLR4 和下游 MCP-1，以及编码血管紧张素原、血管紧张素转换酶、血管紧张素 1 型受体的基因（AT1r）和脑啡肽酶（内普尔）在 nm-cFib 中。 CH拮抗IS启动的nm-cFib激活，但不影响甚至放大其他特征。 IS促进NRF2核转位并表达NRF2靶标Nqo1。与 CH 预孵育和 DN-NRF2 转染均导致 NRF2 核定位丧失。此外，暴露于 IS 后，DN-NRF2 过度表达导致 TLR4 和 MCP-1 水平升高。 IS 引发的 nm-cFib 的 CM 以及在更大程度上 IS+CH 处理的 nm-cFib 的 CM 上调AT1r,内普尔nm-心肌细胞中的 TNFα 和肌生成抑制素基因。因此，IS 部分通过 AhR 触发 nm-cFib 的促炎激活，而 AhR-NRF2 则抵消它。需要除 AhR 抑制以外的策略来针对 IS 对心脏细胞的有害作用。