Charcoal

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.

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.

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

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-1α and microRNA-34a/HNF4α. 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.

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.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) presents with extra-skeletal calcification and renal osteodystrophy (ROD). However, the pathophysiology of ROD remains unclear. Here we examine the hypothesis that stalled mitophagy within osteocytes of CKD-MBD mouse models contributes to bone loss. RNA-seq analysis revealed an altered expression of genes associated with mitophagy and mitochondrial function in tibia of CKD-MBD mice. The expression of mitophagy regulators, p62/SQSTM1, ATG7 and LC3, was inconsistent with functional mitophagy, and in mito-QC reporter mice with ROD, there was a two- to three-fold increase in osteocyte mitolysosomes. To determine if uremic toxins were potentially responsible for these observations, treatment of cultured osteoblasts with uremic toxins revealed increased mitolysosome number and mitochondria with distorted morphology. Membrane potential and oxidative phosphorylation were also decreased, and oxygen-free radical production increased. The altered p62/SQSTM1 and LC3-II expression was consistent with impaired mitophagy machinery, and the effects of uremic toxins were reversible by rapamycin. A causal link between uremic toxins and the development of mitochondrial abnormalities and ROD was established by showing that a mitochondria-targeted antioxidant (MitoQ) and the charcoal adsorbent AST-120 were able to mitigate the uremic toxin-induced mitochondrial changes and improve bone health. Overall, our study shows that impaired clearance of damaged mitochondria may contribute to the ROD phenotype. Targeting uremic toxins, oxygen-free radical production and the mitophagy process may offer novel routes for intervention to preserve bone health in patients with CKD-MBD. This would be timely as our current armamentarium of anti-fracture medications for patients with severe CKD-MBD is limited.