Nakano Takehiro, Kitazato Yutaka, Ogawa Takumu, Tokumaru Kai, Shintani Yuhi, Yoshitake Takuma, Yasuno Kohei, Maeda Hitoshi, Tanaka Motoko, Matsushita Kazutaka, Maruyama Toru, Watanabe Hiroshi
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Clinical Pharmacy and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Kidney360. 2025 May 22. doi: 10.34067/KID.0000000837.
The relationship between the progression of chronic kidney disease (CKD) and trace element deficiencies has attracted considerable attention. However, many aspects of trace element deficiency and the molecular mechanisms of CKD pathology remain unclear. Here, we hypothesized that uremic toxins are involved in trace element deficiencies, which contribute to the progression of CKD.
Adenine-induced CKD mice were used for in vivo study. Cultured hepatocytes were used for in vitro study.
Seventeen trace elements in the plasma of CKD mice were measured using inductively coupled plasma mass spectrometry. Among these, selenium was identified as the trace element most significantly affected by the administration of AST-120, an oral spherical activated carbon. CKD mice displayed reduced levels of selenium in the plasma, which was restored after the administration of AST-120. In vivo and in vitro experiments showed the uremic toxin indoxyl sulfate (IS) decreased expression of the selenium transport protein SEPP1 in liver. IS suppressed SEPP1 expression through increased production of reactive oxygen species (ROS) via the OATP/AhR/NADPH oxidase pathway. Increased ROS led to the downregulation of transcription factors for SEPP1, such as AMPK/PGC1-α and miR-34a/HNF4α. Analysis of serum from hemodialysis patients also suggested that IS is involved in reducing serum SEPP1 levels and exacerbating selenium deficiency. Combination therapy with AST-120 and sodium selenite restored the supply of selenium to the kidneys and increased GPX4 expression, thereby exerting renoprotective effects via suppression of ferroptosis.
This study highlights the key role IS plays in selenium deficiency and renal ferroptosis by suppressing hepatic SEPP1 expression. The findings suggest potential therapeutic strategies that target IS and selenium deficiency for the management of CKD.
慢性肾脏病（CKD）进展与微量元素缺乏之间的关系已引起广泛关注。然而，微量元素缺乏的诸多方面以及CKD病理的分子机制仍不清楚。在此，我们推测尿毒症毒素参与微量元素缺乏，这有助于CKD的进展。
使用腺嘌呤诱导的CKD小鼠进行体内研究。使用培养的肝细胞进行体外研究。
采用电感耦合等离子体质谱法测定CKD小鼠血浆中的17种微量元素。其中，硒被确定为受口服球形活性炭AST - 120给药影响最显著的微量元素。CKD小鼠血浆中硒水平降低，给予AST - 120后恢复。体内和体外实验表明，尿毒症毒素硫酸吲哚酚（IS）降低肝脏中硒转运蛋白SEPP1的表达。IS通过OATP/AhR/ NADPH氧化酶途径增加活性氧（ROS）的产生来抑制SEPP1表达。ROS增加导致SEPP1转录因子如AMPK/PGC1 -α和miR - 34a/HNF4α的下调。对血液透析患者血清的分析也表明，IS参与降低血清SEPP1水平并加剧硒缺乏。AST - 120和亚硒酸钠联合治疗恢复了肾脏的硒供应并增加了GPX4表达，从而通过抑制铁死亡发挥肾脏保护作用。
本研究强调了IS通过抑制肝脏SEPP1表达在硒缺乏和肾脏铁死亡中所起的关键作用。这些发现提示了针对IS和硒缺乏管理CKD的潜在治疗策略。
