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

Abstract

Wen-Ching Shen,1 Yu-Hsiang Chou,2 Li-Shian Shi,3 Zhi-wei Chen,4 Hai-Jian Tu,4 Xin-yi Lin,1 Guei-Jane Wang5– 8 1Department of Basic Medicine, Putian University, Putian City, Fujian Province, People’s Republic of China; 2Department of Internal Medicine, National Taiwan University Hospital Jin-Shan Branch, New Taipei City, Taiwan; 3Department of Biotechnology, National Formosa University, Yun-Lin, Taiwan; 4The Affiliated Hospital of Putian University, Putian City, Fujian Province, People’s Republic of China; 5School of Medicine, Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 40402, Taiwan; 6School of Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan; 7Department of Medical Research, China Medical University Hospital, Taichung, 40447, Taiwan; 8Department of Health and Nutrition Biotechnology, Asia University, Taichung, 41354, TaiwanCorrespondence: Guei-Jane WangSchool of Medicine, Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 40402, TaiwanTel [phone] ext. 4727Fax [phone]Email [email protected] ShenDepartment of Basic Medicine, Putian University, 1133 Xueyuan Road, Chengxiang District, Putian City, Fujian Province, 351100, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]: 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 and Methods: 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.Results: 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.Conclusion: 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.Keywords: acute kidney injury, cardiac dysfunction, AST-120, inflammation, apoptosis, NF-κB

Keywords

• acute kidney injury
• cardiac dysfunction
• ast-120
• inflammation
• apoptosis
• nf-b.