Indoxyl Sulfate Contributes to Selenium Deficiency and Renal Ferroptosis by Decreasing the Expression of Selenium Transport Protein SEPP1.

Abstract

Background: 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.

Methods: Adenine-induced CKD mice were used for in vivo study. Cultured hepatocytes were used for in vitro study.

Results: 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.

Conclusions: 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.