INDOXYL SULFATE DOWNREGULATES HEPATIC SEPP1 LEADING TO SELENIUM DEFICIENCY AND RENAL FERROPTOSIS

The relationship between the progression of CKD and trace element deficiencies has attracted considerable attention. However, the specific mechanisms linking trace element deficiency to CKD pathology remain unclear. In this study, we investigated the effects of uremic toxins on trace element deficiencies and their pathophysiology.

Adenine-induced CKD mice were treated with oral spherical activated carbon (AST-120), an adsorbent that removes uremic toxins from the gut. Cultured hepatocytes were used for in vitro study. Trace elements were measured by inductively coupled plasma mass spectrometry (ICP-MS).

Among seventeen trace elements in the plasma of CKD mice, selenium (Se) was identified as the element most significantly restored by the administration of AST-120. The plasma Se concentration showed a negative correlation with the uremic toxin indoxyl sulfate (IS). In vivo and in vitro experiments demonstrated that IS decreased expression of the Se transport protein selenoprotein P (SEPP1) in the liver. The decrease in hepatic SEPP1 expression was associated with increased urinary Se excretion and reduced Se content in kidney tissue. Furthermore, reduced expression of the selenium-containing protein GPX4 and ferroptosis were observed in the renal tissue of CKD mice, both of which were suppressed by AST-120.

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.

Portions of this data were presented at The 68th Annual Meeting of the Japanese Society of Nephrology.