Yan Liu1, Yanming Yu2, Jicheng Zhang3, Chunting Wang4. 1. Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250000, China; Department of Infectious Disease, The Affiliated Yantai Yuhuangding Hospital of Qingdao University Institution, Yantai, Shandong, China. 2. Department of Nephrology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China. 3. Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250000, China. Electronic address: jczhangicu@163.com. 4. Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250000, China. Electronic address: wangchuntingicu@163.com.
Abstract
BACKGROUND: Sepsis is an inflammatory response undergoing the complicate pathophysiological changes for host defense against pathogens. Previous studies suggested that dexmedetomidine (DEX) was served to controlling the over-reactive inflammatory effects to protect from the sepsis-induced organ failure via modulating histone methylation. However, the genome-wide changes of histone methylations upon DEX for sepsis treatment were poorly explored. MATERIALS AND METHODS: The acute kidney injury (AKI) mouse model were induced by lipopolysaccharide (LPS). DEX and KDM5 (H3K4 demethylases) inhibitors were used to add additionally. H3K4me3 antibody was used to conduct the ChIP-seq assay in renal cortex tissues. RESULTS: We observed that the overall H3K4me3 levels were obviously declined in AKI group compared to the normal control. We further observed that the therapeutic effect of DEX was basically equal with CPI-455 and KDM5A-IN-1 but better than PBIT. The overall H3K4me3 level was reduced in AKI group compared to DEX (p = 0.008), and KDM5A-IN-1 groups (p = 0.022). The H3K4me3 enrichment of the multiple genes associated with inflammatory cytokines such as TNF-α, NOS2 and CCL2 increased in AKI model, but decreased upon DEX or KDM5A-IN-1 treatment. Consistently, transcription and protein levels of genes such as TLR4, MYD88, MTA1, PTGS2, CASP3 associated with NF-κB signaling pathway were all compromising after treated with DEX or KDM5A-IN-1 groups compared to AKI group. CONCLUSION: Taken together, our data determined that DEX could attenuate AKI through KDM5A inhibition in sepsis.
BACKGROUND:Sepsis is an inflammatory response undergoing the complicate pathophysiological changes for host defense against pathogens. Previous studies suggested that dexmedetomidine (DEX) was served to controlling the over-reactive inflammatory effects to protect from the sepsis-induced organ failure via modulating histone methylation. However, the genome-wide changes of histone methylations upon DEX for sepsis treatment were poorly explored. MATERIALS AND METHODS: The acute kidney injury (AKI) mouse model were induced by lipopolysaccharide (LPS). DEX and KDM5 (H3K4 demethylases) inhibitors were used to add additionally. H3K4me3 antibody was used to conduct the ChIP-seq assay in renal cortex tissues. RESULTS: We observed that the overall H3K4me3 levels were obviously declined in AKI group compared to the normal control. We further observed that the therapeutic effect of DEX was basically equal with CPI-455 and KDM5A-IN-1 but better than PBIT. The overall H3K4me3 level was reduced in AKI group compared to DEX (p = 0.008), and KDM5A-IN-1 groups (p = 0.022). The H3K4me3 enrichment of the multiple genes associated with inflammatory cytokines such as TNF-α, NOS2 and CCL2 increased in AKI model, but decreased upon DEX or KDM5A-IN-1 treatment. Consistently, transcription and protein levels of genes such as TLR4, MYD88, MTA1, PTGS2, CASP3 associated with NF-κB signaling pathway were all compromising after treated with DEX or KDM5A-IN-1 groups compared to AKI group. CONCLUSION: Taken together, our data determined that DEX could attenuate AKI through KDM5A inhibition in sepsis.
Authors: Steven Menez; Wenjun Ju; Rajasree Menon; Dennis G Moledina; Heather Thiessen Philbrook; Eric McArthur; Yaqi Jia; Wassim Obeid; Sherry G Mansour; Jay L Koyner; Michael G Shlipak; Steven G Coca; Amit X Garg; Andrew S Bomback; John A Kellum; Matthias Kretzler; Chirag R Parikh Journal: JCI Insight Date: 2021-06-08