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

Wen-Ching Shen; Yu-Hsiang Chou; Li-Shian Shi; Zhi-Wei Chen; Hai-Jian Tu; Xin-Yi Lin; Guei-Jane Wang

doi:10.2147/JIR.S283378

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

J Inflamm Res. 2021 Feb 24:14:505-518. doi: 10.2147/JIR.S283378. eCollection 2021.

Authors

Wen-Ching Shen¹, Yu-Hsiang Chou², Li-Shian Shi³, Zhi-Wei Chen⁴, Hai-Jian Tu⁴, Xin-Yi Lin¹, Guei-Jane Wang^{5

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Affiliations

¹ Department of Basic Medicine, Putian University, Putian City, Fujian Province, People's Republic of China.
² Department of Internal Medicine, National Taiwan University Hospital Jin-Shan Branch, New Taipei City, Taiwan.
³ Department of Biotechnology, National Formosa University, Yun-Lin, Taiwan.
⁴ The Affiliated Hospital of Putian University, Putian City, Fujian Province, People's Republic of China.
⁵ School of Medicine, Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 40402, Taiwan.
⁶ School of Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan.
⁷ Department of Medical Research, China Medical University Hospital, Taichung, 40447, Taiwan.
⁸ Department of Health and Nutrition Biotechnology, Asia University, Taichung, 41354, Taiwan.

Abstract

Purpose: 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: AST-120; NF-κB; acute kidney injury; apoptosis; cardiac dysfunction; inflammation.

Grants and funding

This work was supported by the Ministry of Science and Technology to YHC (MOST 104-2314-B-002-119-MY3) and GJW (MOST 108-2635-B-039-002), respectively; China Medical University (CMU108-MF-18) and China Medical University Hospital (DMR-107-113) to GJW; and Putian University (2019118) and Mrs. Hsiu-Chin Lee Kidney Research Foundation to WCS.