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Inhibition of Histone H3K27 Acetylation Orchestrates Interleukin-9-Mediated and Plays an Anti-Inflammatory Role in Cisplatin-Induced Acute Kidney Injury.

ABSTRACT: Nephrotoxicity is a major side effect of cisplatin (CP)- and platinum-related chemotherapy, and inflammation contributes to disease pathogenesis. Interleukin-9 (IL-9) is a pleiotropic cytokine associated with inflammation. Here, we investigated the key role of IL-9 as a regulator of protective mechanisms in CP-induced acute kidney injury (AKI). We observed that IL-9 was decreased not only in a CP-induced AKI mouse model but also in THP-1 and RAW264.7 cell lines. Seventy-two hours post-CP injection, renal dysfunction and tubule injury were significantly attenuated in IL-9 overexpression adeno-associated virus 9 (AAV9)-treated mice. The levels of serum urea, serum creatinine, kidney injury molecule-1 (KIM-1), and histological damage were partially diminished following treatment with IL-9. The renoprotective effects of IL-9 may be attributed to the regulation of cytokines, and we found that IL-9 acted on macrophages in a regulatory manner, promoting an anti-inflammatory phenotype. Furthermore, IL-9 enhanced the suppression of macrophage-driven renal inflammation. Inhibition of H3K27 acetylation orchestrated IL-9-mediated renoprotection in CP-induced AKI. Thus, our findings indicate novel and potent anti-inflammatory properties of IL-9 that confer preservation of kidney function and structure in CP-induced AKI, which may counteract kidney disease procession.

SUBMITTER: Jiang W

PROVIDER: S-EPMC7062682 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Inhibition of Histone H3K27 Acetylation Orchestrates Interleukin-9-Mediated and Plays an Anti-Inflammatory Role in Cisplatin-Induced Acute Kidney Injury.

Jiang Wenjuan W Yuan Xinrong X Zhu Hong H He Changsheng C Ge Caiqiong C Tang Qing Q Xu Chuanting C Hu Bingfeng B Huang Cheng C Ma Taotao T

Frontiers in immunology 20200303

Nephrotoxicity is a major side effect of cisplatin (CP)- and platinum-related chemotherapy, and inflammation contributes to disease pathogenesis. Interleukin-9 (IL-9) is a pleiotropic cytokine associated with inflammation. Here, we investigated the key role of IL-9 as a regulator of protective mechanisms in CP-induced acute kidney injury (AKI). We observed that IL-9 was decreased not only in a CP-induced AKI mouse model but also in THP-1 and RAW264.7 cell lines. Seventy-two hours post-CP injecti ...[more]

PMID: 32194547

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Project description:Despite clinical advances, ischemia-induced cardiac diseases remain an underlying cause of death worldwide. Epigenetic modifications, especially alterations in the acetylation of histone proteins play a pivotal role in counteracting stressful conditions, including ischemia. In our study, we found that histone active mark H3K27ac was significantly reduced and histone repressive mark H3K27me3 was significantly upregulated in the cardiomyocytes exposed to the ischemic condition. Then, we performed a high throughput drug screening assay using rat ventricular cardiomyocytes during the ischemic condition and screened an antioxidant compound library comprising of 84 drugs for H3K27ac by fluorescence microscopy. Our data revealed that most of the phenolic compounds like eugenol, apigenin, resveratrol, bis-demethoxy curcumin, D-gamma-tocopherol, ambroxol, and non-phenolic compounds like l-Ergothioneine, ciclopirox ethanolamine, and Tanshinone IIA have a crucial role in maintaining the cellular H3K27ac histone marks during the ischemic condition. Further, we tested the role of eugenol on cellular protection during ischemia. Our study shows that ischemia significantly reduces cellular viability and increases total reactive oxygen species (ROS), and mitochondrial ROS in the cells. Interestingly, eugenol treatment significantly restores the cellular acetylation at H3K27, decreases cellular ROS, and improves cellular viability. To explore the mechanism of eugenol-medicated inhibition of deacetylation, we performed a RNAseq experiment. Analysis of transcriptome data using IPA indicated that eugenol regulates several cellular functions associated with cardiovascular diseases, and metabolic processes. Further, we found that eugenol regulates the expression of HMGN1, CD151 and Ppp2ca genes during ischemia. Furthermore, we found that eugenol might protect the cells from ischemia through modulation of HMGN1 protein expression, which plays an active role in regulation of histone acetylation and cellular protection during stress. Thus, our study indicated that eugenol can be exploited as an agent to protect the ischemic cells and also could be used to develop a novel drug for treating cardiac disease.

Dataset Information

Inhibition of Histone H3K27 Acetylation Orchestrates Interleukin-9-Mediated and Plays an Anti-Inflammatory Role in Cisplatin-Induced Acute Kidney Injury.

Publications

Inhibition of Histone H3K27 Acetylation Orchestrates Interleukin-9-Mediated and Plays an Anti-Inflammatory Role in Cisplatin-Induced Acute Kidney Injury.

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