Early elimination of uremic toxin ameliorates AKI-to-CKD transition. Issue 23 (10th December 2021)

• Record Type: Journal Article
• Authors: Chen, Jia-Huang; Chao, Chia-Ter; Huang, Jenq-Wen; Hung, Kuan-Yu; Liu, Shing-Hwa; Tarng, Der-Cherng; Chiang, Chih-Kang
• Is Part Of: Clinical science. Volume 135:Issue 23(2021)
• Page Start: 2643
• Page End: 2658
• Publication Date: 2021-12-10
• Subjects: AKI to CKD -- AST-120 -- ER stress -- indoxyl sulfate -- unfolded protein response; Medicine -- Periodicals; Biochemistry -- Periodicals; 616
• DOI: 10.1042/CS20210858
• Languages: English
• ISSNs: 0143-5221

Abstract

Abstract: Acute kidney injury (AKI)-related fibrosis is emerging as a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still poorly understood. 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 present study aims to elucidate the effects of IS on tubular damage and its involvement 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 (UIRI) without a contralateral nephrectomy model. Serum IS is positively correlated with renal fibrosis and binding immunoglobulin protein (BiP) and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) 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 endoplasmic reticulum (ER) stress, 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 (EMT) and aggravated ER stress induction in vitro . Finally, the ER chemical chaperon, 4-phenylbutyric acid (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 and/or treatment of the AKI-to-CKD transition.