AST-120 Improves Cardiac Dysfunction in Acute Kidney Injury Mice via Suppression of Apoptosis and Proinflammatory NF-κB/ICAM-1 Signaling

• Published in: Journal of inflammation research 2021-01, Vol.14, p.505-518
• Main Authors: Shen, Wen-Ching, Chou, Yu-Hsiang, Shi, Li-Shian, Chen, Zhi-Wei, Tu, Hai-Jian, Lin, Xin-Yi, Wang, Guei-Jane
• Format: Article
• Language: English
• Subjects: acute kidney injury; Antibodies; Apoptosis; ast-120; cardiac dysfunction; Cardiomyocytes; Cell adhesion & migration; Cell culture; Chromatography; Creatinine; Cytokines; Echocardiography; Endothelial cells; Heart; Hospitals; IL-1β; Inflammation; Intercellular adhesion molecule 1; Ischemia; Kidneys; Laboratory animals; Morbidity; NF-κB protein; nf-b; Oral administration; Original Research; Oxidative stress; Peptides; Plasma; Plasma levels; Reperfusion; Sulfates; Toxins; Transcription factors; Umbilical vein; Urea
• ISSN: 1178-7031; 1178-7031
• DOI: 10.2147/JIR.S283378

Acute kidney injury (AKI) is a devastating disorder associated with considerably high morbidity and mortality. Reports have shown that AST-120, an oral charcoal adsorbent, can reduce oxidative stress by lowering serum indoxyl sulfate levels. The effects of AST-120 and indoxyl sulfate on kidney injury and cardiac dysfunction were investigated in vivo and in vitro. Patients were tracked for enrollment upon receiving a diagnosis of AKI. Plasma was collected to determine the renal and inflammatory parameters. Renal ischemia/reperfusion (I/R) induced AKI or sham operation was performed in C57BL/6J mice. Animals were divided into sham, AKI+vehicle, and AKI+AST-120 groups. Plasma and tissues were assembled after 48 h to assess apoptotic and inflammatory responses. We also conducted human umbilical vein endothelial cell (HUVECs) and HL-1 cardiomyocyte culture studies to determine the underlying mechanisms of indoxyl sulfate's effects. Echocardiography, histopathology, biochemical indexes, ELISA, terminal dUTP nick-end labeling (TUNEL) and Western blot analysis were performed. The cohort included 25 consecutive patients with AKI and 25 non-AKI. Plasma levels of creatinine, indoxyl sulfate, IL-1β and ICAM-1 were significantly higher in patients with AKI than in non-AKI controls. Plasma levels of blood urea nitrogen, creatinine, indoxyl sulfate, IL-1β and renal tubular injury were increased in mice after renal I/R and were decreased by AST-120 treatment. In addition, AST-120 therapy not only improved the parameters assessed by echocardiography but also substantially attenuated the elevation of plasma BNP. Oral administration of AST-120 significantly downregulated NF-κB/ICAM-1 expression and reduced cell apoptosis in both kidney and heart after renal I/R injury. Our investigations demonstrated that AST-120 administration improves cardiac dysfunction in AKI mice via the suppression of apoptosis and proinflammatory NF-κB/ICAM-1 signaling.