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

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.

• Authors: Jia-Huang Chen, Chia-Ter Chao, Jenq-Wen Huang, Kuan-Yu Hung, Shing-Hwa Liu, Der-Cherng Tarng, Chih-Kang Chiang
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 135 Issue 23 Pg. 2643-2658 (12 10 2021) ISSN: 1470-8736 [Electronic] England
• PMID: 34796904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• 4-phenylbutylamine
• Butylamines
• Oxides
• Carbon
• AST 120
• Indican

Topics

• Acute Kidney Injury (blood, complications)
• Animals
• Butylamines
• Carbon (pharmacology, therapeutic use)
• Drug Evaluation, Preclinical
• Indican (antagonists & inhibitors, blood, isolation & purification)
• Mice, Inbred C57BL
• Nephrosclerosis (blood, etiology, prevention & control)
• Oxides (pharmacology, therapeutic use)
• Renal Insufficiency, Chronic (etiology, prevention & control)
• Reperfusion Injury (blood, etiology)
• Senescence-Associated Secretory Phenotype (drug effects)
• Unfolded Protein Response (drug effects)