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

Clin Sci (Lond). 2021 Dec 10;135(23):2643-2658. doi: 10.1042/CS20210858.

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.

Keywords: AKI to CKD; AST-120; ER stress; indoxyl sulfate; unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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