Alcohol promotes renal fibrosis by activating Nox2/4-mediated DNA methylation of Smad7
| Autor: | Xiao-Ming Meng, Jia-gen Wen, Biao Wei, Hai-Yong Chen, Qin Yang, Jia-Nan Wang, Xue-Qi Liu, Jun Li, Juan Jin, Wei-Jian Ni, Ling Jiang, Huai-Qin Han, Yan Huang, Wei-Feng Wu, Li Gao, Qiu-Ying Ma, Taotao Ma, Qi Chen |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
DNA (Cytosine-5-)-Methyltransferase 1 Male medicine.medical_specialty Bisulfite sequencing medicine.disease_cause Kidney Models Biological Cell Line Smad7 Protein Transforming Growth Factor beta1 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Renal fibrosis Animals Humans Smad3 Protein integumentary system Ethanol Chemistry NOX4 Acetophenones Reproducibility of Results Epithelial Cells General Medicine Methylation DNA Methylation medicine.disease Fibrosis Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology Kidney Tubules Liver NADPH Oxidase 4 030220 oncology & carcinogenesis DNA methylation Apocynin NADPH Oxidase 2 Kidney Diseases Reactive Oxygen Species Oxidative stress Kidney disease Signal Transduction |
| Zdroj: | Clinical science (London, England : 1979). 134(2) |
| ISSN: | 1470-8736 |
| Popis: | Alcohol consumption causes renal injury and compromises kidney function. The underlying mechanism of the alcoholic kidney disease remains largely unknown. In the present study, an alcoholic renal fibrosis animal model was first employed which mice received liquid diet containing alcohol for 4 to 12 weeks. The Masson’s Trichrome staining analysis showed that kidney fibrosis increased at week 8 and 12 in the animal model that was further confirmed by albumin assay, Western blot, immunostaining and real-time PCR of fibrotic indexes (collagen I and α-SMA). In vitro analysis also confirmed that alcohol significantly induced fibrotic response (collagen I and α-SMA) in HK2 tubular epithelial cells. Importantly, both in vivo and in vitro studies showed alcohol treatments decreased Smad7 and activated Smad3. We further determined how the alcohol affected the balance of Smad7 (inhibitory Smad) and Smad3 (regulatory Smad). Genome-wide methylation sequencing showed an increased DNA methylation of many genes and bisulfite sequencing analysis showed an increased DNA methylation of Smad7 after alcohol ingestion. We also found DNA methylation of Smad7 was mediated by DNMT1 in ethyl alcohol (EtOH)-treated HK2 cells. Knockdown of Nox2 or Nox4 decreased DNMT1 and rebalanced Smad7/Smad3 axis, and thereby relieved EtOH-induced fibrotic response. The inhibition of reactive oxygen species by the intraperitoneal injection of apocynin attenuated renal fibrosis and restored renal function in the alcoholic mice. Collectively, we established novel in vivo and in vitro alcoholic kidney fibrosis models and found that alcohol induces renal fibrosis by activating oxidative stress-induced DNA methylation of Smad7. Suppression of Nox-mediated oxidative stress may be a potential therapy for long-term alcohol abuse-induced kidney fibrosis. |
| Databáze: | OpenAIRE |
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