期刊
CLINICAL SCIENCE
卷 135, 期 23, 页码 2643-2658出版社
PORTLAND PRESS LTD
DOI: 10.1042/CS20210858
关键词
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资金
- Ministry of Science and Technology of Taiwan [MOST-104-2314-B-002-126-MY3, 107-2314-B-002 -027 -MY3, 110-2314-B-002 -130]
- National Taiwan University [NTUH-106-S3574, NTUH-107-S3826, NTUH -110-S5063]
- Taipei Veterans General Hospital-National Taiwan University Hospital Joint Research Program [TVGH-NTUH-VN107-18]
The study reveals that the accumulation of IS is associated with renal fibrosis and upregulation of BiP and CHOP. Administration of indole, a precursor of IS, exacerbates renal fibrosis, SASP, and activation of ER stress, while AST-120 attenuates these effects.
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.
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