Early elimination of uremic toxin ameliorates AKI-to-CKD transition

Abstract

Acute kidney injury (AKI)-related fibrosis is a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still unclear. The accumulation of indoxyl sulfate (IS), a protein-bound uremic toxin, has been identified as a detrimental factor of renal fibrosis. However, the mechanisms underlying IS-related aberrant kidney recovery after AKI is still unknown. The study aims to elucidate the effects of IS in the pathogenesis of AKI to CKD transition. Our results showed that serum IS started to accumulate associated with the downregulation of tubular organic anion transporter, but not observed in the small-molecule uremic toxins of the unilateral ischemia-reperfusion injury without a contralateral nephrectomy model(UIRI). Serum IS is positively correlated with renal fibrosis and ER stress-related protein expression induction in the UIRI with a contralateral nephrectomy model (UIRI+Nx). To evaluate the effects of IS in the AKI to CKD transition, we administered indole, a precursor of IS, at the early stage of UIRI. Our results demonstrated IS potentiates renal fibrosis, senescence-associated secretory phenotype (SASP), and activation of ER, which is attenuated by synergistic AST-120 administration. Furthermore, we clearly demonstrated that IS exposure potentiated hypoxia-reperfusion (H/R) induced G2/M cell cycle arrest, epithelial-mesenchymal transition, and aggravated ER stress induction in vitro. Finally, the ER chemical chaperon, 4-PBA, successfully reversed the above-mentioned AKI to CKD transition. Taken together, early IS elimination in the early stage of AKI is likely to be a useful strategy in the prevention or treatment of the AKI to CKD transition.

Uremic Toxins and Protein-Bound Therapeutics in AKI and CKD: Up-to-Date Evidence

“…It has been found that IS accumulates in an in vivo AKI model [29,31]. Different to BUN and sCr levels which return to normal levels in the recovery stage of AKI [25], furthermore, our current work found that accumulation of the secreted PBUT is sustained without an increase in BUN and sCr after 10 days of unilateral ischemia-reperfusion injury mice model [32]. Therefore, we thought UIRI model would be a suitable model to investigate the roles of PBUTs in AKI to CKD transition.…”

“…During exposure to PBUTs, fibroblasts are directly activated by IS or PCS stimulation or indirectly by tubular secreted TGF-β then leading to myofibroblast activation and extracellular matrix deposition [52][53][54]. Chen et al indicated that oral gavage of the IS precursor-indole accelerated AKI to CKD progression in an ER stress-dependent manner [32]. Furthermore, several studies support the concept that AKI insults promote premature aging development [55,56].…”

“…Currently, the concept of uremic toxins' early elimination has been proposed in several studies. Chen et al found that oral intake of AST-120 can alleviate IS accumulation-induced renal fibrosis and ER stress in a two-stage IRI model [32]. Shen et al demonstrated that the AST-120 administration in a mouse IRI model improved cardiac dysfunction through IS-mediated NF-κB/ICAM-1 proinflammatory signaling and apoptosis (Table 1) [74].…”

The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition

“…The cell growth and proliferation ability were measured with CellTiter 96 ® Aqueous One Solution Cell Proliferation kit (Promega). The detailed procedure was described as previous [ 30 ]. Briefly, HK-2 cells were plated in a 96-well plate.…”

The Role of Gut-Derived, Protein-Bound Uremic Toxins in the Cardiovascular Complications of Acute Kidney Injury

“…However, the association between IS, cardiovascular dysfunction, and cardiovascular complications can also be explained by the pathological action of IS on kidney disease progression. Indeed, several experimental studies have highlighted the effect of IS on the development of renal fibrosis through oxidative stress, the activation of endoplasmic reticulum stress, and the epithelial-mesenchymal transition [ 80 , 81 , 82 , 83 , 84 , 85 ].…”