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.

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