Annual Meeting of the Japanese Society of Toxicology
The 51st Annual Meeting of the Japanese Society of Toxicology
Session ID : P-99S
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Poster Session
Screening for compounds that inhibit chronic kidney disease-induced cardiac inflammation and fibrosis
*Miyu SAKUGAWAYuya YOSHIDAKohei FUKUOKAKurumi SOTONOTomohito TANIHARANaoki NISHIKAWAFumiaki TSURUSAKITakumi NISHIYuka KAIDOAkito TSURUTAKengo HAMAMURASatoru KOYANAGIShigehiro OHDONaoya MATSUNAGA
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Abstract

Introduction: Chronic kidney disease (CKD) is associated with several complications, especially heart failure (HF) which is a major cause of death. However, there is no effective treatment to control it. In contrast, we revealed that G protein coupled receptor 68 (GPR68), which is highly expressed on macrophages, exacerbates cardiac inflammation and fibrosis in CKD. In this study, we explored GPR68 inhibitors to prevent or improve CKD associated HF1 .

Method: We established an evaluation system in which GPR68 activity can be detected by luciferase activity using MDA-MB-231 cells and used High throughput screening (HTS) to search for compounds with human GPR68 inhibitory activity.

We used the 5/6 nephrectomy (5/6Nx) ICR mouse as CKD mouse model.

Result: We used HTS dependent on nuclear factor of activated T cells response element luciferase activity and toxicity test to screen for GPR68 inhibitors. Then, we identified the GPR68 inhibitory extract which significantly suppressed inflammatory cytokines in RAW264.7 with GPR68 high expression. Afterwards, we analyzed pathology of 5/6Nx mice administrated the extracts water. As result, the extracts significantly not only suppressed upregulation of cytokines, fibrosis and BNP levels, but also improved weight loss and survival rate in 5/6Nx mice. Furthermore, we identified the inhibitory compound among the alkaloids from extracts and this compound had anti-inflammatory effects as well as extracts. Finally, we found out the extracts and compound suppressed inflammatory cytokines and cardiac fibrosis via inhibition of GPR68 in CKD.

1. Sakugawa M, et al., Trans Res., 2024

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© 2024 The Japanese Society of Toxicology
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