Dataset Information

METTL3/m6A/miRNA-873-5p Attenuated Oxidative Stress and Apoptosis in Colistin-Induced Kidney Injury by Modulating Keap1/Nrf2 Pathway.

ABSTRACT: Nephrotoxicity of colistin is the major factor limiting its clinical application. However, the exact mechanism of colistin-induced nephrotoxicity is still elusive. N6-Methyladenosine (m6A) modification has been implicated in many biological processes, however, its role in colistin-induced nephrotoxicity needs to be elucidated. Mouse renal tubular epithelial cells (mRTECs) were treated with 200 ?M colistin with or without METTL3 overexpression. Cells injury, m6A assay, oxidative stress and apoptosis were examined. Levels of m6A are decreased after colistin treatment in mRTECs. METTL3 is the major factor involved in abnormal m6A modification. METTL3 overexpression plays a protective role against colistin-induced oxidative stress and apoptosis. Moreover, METTL3 interacts with the microprocessor protein DGCR8 and positively modulates miR-873-5p mature process in an m6A-dependent manner. Further experiments show that miR-873-5p could regulate Keap1-Nrf2 pathway against colistin-induced oxidative stress and apoptosis. These studies revealed an important role of METTL3/m6A in colistin-induced nephrotoxicity and provide a new insight on m6A modification in drug induced toxicity.

SUBMITTER: Wang J

PROVIDER: S-EPMC6530351 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

METTL3/m6A/miRNA-873-5p Attenuated Oxidative Stress and Apoptosis in Colistin-Induced Kidney Injury by Modulating Keap1/Nrf2 Pathway.

Wang Jian J Ishfaq Muhammad M Xu Liang L Xia Chunli C Chen Chunli C Li Jichang J

Frontiers in pharmacology 20190515

Nephrotoxicity of colistin is the major factor limiting its clinical application. However, the exact mechanism of colistin-induced nephrotoxicity is still elusive. N6-Methyladenosine (m6A) modification has been implicated in many biological processes, however, its role in colistin-induced nephrotoxicity needs to be elucidated. Mouse renal tubular epithelial cells (mRTECs) were treated with 200 μM colistin with or without METTL3 overexpression. Cells injury, m6A a ...[more]

PMID: 31156435

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Project description:BackgroundCardiac remodeling is a common pathological feature in many cardiac diseases, characterized by cardiac hypertrophy and fibrosis. Triptolide (TP) is a natural compound derived from Tripterygium wilfordii Hook F. However, the related mechanism of it in cardiac remodeling has not been fully understood.Methods and resultsTransverse aortic constriction (TAC)-induced cardiac hypertrophic mouse model and angiotensin II (Ang II)-induced cardiomyocytes hypertrophic model were performed. Firstly, the results indicate that TP can improve cardiac function, decreased cardiomyocyte surface area and fibrosis area, as well as lowered the protein expressions of brain natriuretic peptide (BNP), β-major histocompatibility complex (β-MHC), type I and III collagen (Col I and III). Secondly, TP suppressed cardiac pyroptosis, and decreased the levels of Interleukin-1β (IL-1β), Interleukin-18 (IL-18) by Enzyme-linked immunosorbent assay (ELISA), and pyroptosis-associated proteins. Furthermore, TP enhanced the expressions of Nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase 1 (HO-1). Interestingly, when Nrf2 was silenced by siRNA, TP lost its properties of reducing pyroptosis and cardiac hypertrophy. In addition, in the Transforming Growth Factor β1 (TGF-β1)-induced primary human coronary artery endothelial cells (HCAEC) model, TP was found to inhibit the process of endothelial-to-mesenchymal transition (EndMT), characterized by the loss of endothelial-specific markers and the gain of mesenchymal markers. This was accompanied by a suppression of Slug, Snail, and Twist expression. Meanwhile, the inhibitory effect of TP on EndMT was weakened when Nrf2 was silenced by siRNA. Lastly, potential targets of TP were identified through network pharmacology analysis, and found that Ubiquitin-Specific Protease 14 (USP14) was one of them. Simultaneously, the data indicated that decrease the upregulation of USP14 and Kelch-like ECH-Associated Protein 1 (Keap1) caused by cardiac remodeling. However, Keap1 was decreased and Nrf2 was increased when USP14 was silenced. Furthermore, CoIP analysis showed that USP14 directly interacts with Keap1.ConclusionTP can observably reduce pyroptosis and EndMT by targeting the USP14/Keap1/Nrf2 pathway, thereby significantly attenuating cardiac remodeling.

Dataset Information

METTL3/m6A/miRNA-873-5p Attenuated Oxidative Stress and Apoptosis in Colistin-Induced Kidney Injury by Modulating Keap1/Nrf2 Pathway.

Publications

METTL3/m<sup>6</sup>A/miRNA-873-5p Attenuated Oxidative Stress and Apoptosis in Colistin-Induced Kidney Injury by Modulating Keap1/Nrf2 Pathway.

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