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

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Key Points Indoxyl sulfate (IS) is involved in the liver-kidney axis by inducing renal ferroptosis by selenium deficiency due to suppression of selenoprotein P (SEPP1) expression in the liver. IS concentrations were negatively associated with selenium concentrations and SEPP1 concentrations in serum from patients on dialysis. We propose the potential therapeutic strategy targeting the IS/SEPP1/glutathione peroxidase 4 pathway for CKD. Background The relationship between the progression of 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. In this study, 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 plasma of CKD mice were measured using inductively coupled plasma mass spectrometry. Among these, selenium (Se) was identified as the trace element most significantly affected by the administration of oral spherical activated carbon (AST-120), an oral spherical activated carbon. CKD mice displayed reduced levels of Se in 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 Se transport protein selenoprotein P (SEPP1) in the liver. IS suppressed SEPP1 expression through increased production of reactive oxygen species by the organic anion transporting polypeptide/aryl hydrocarbon receptor/NADPH oxidase pathway. Increased reactive oxygen species led to the downregulation of transcription factors for SEPP1, such as AMP-activated protein kinase/PGC-1 α and microRNA-34a/HNF4 α . Analysis of serum from patients on hemodialysis also suggested that IS is involved in reducing serum SEPP1 levels and exacerbating Se deficiency. Combination therapy with AST-120 and sodium selenite restored the supply of Se to the kidneys and increased glutathione peroxidase 4 expression, thereby exerting renoprotective effects by suppression of ferroptosis. Conclusions This study highlights the key role IS plays in Se deficiency and renal ferroptosis by suppressing hepatic SEPP1 expression. The findings suggest potential therapeutic strategies that target IS and Se deficiency for the management of CKD.