Meclofenamic acid promotes cisplatin-induced acute kidney injury by inhibiting fat mass and obesity-associated protein-mediated m6A abrogation in RNA
| Autor: | Qingqing Xu, Ming Wu, Peihui Zhou, Li Wang, Chaoyang Ye |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Alpha-Ketoglutarate-Dependent Dioxygenase FTO Apoptosis urologic and male genital diseases Biochemistry Cell Line Mice 03 medical and health sciences In vivo Internal medicine medicine Animals Humans Molecular Biology Meclofenamic Acid Cisplatin Messenger RNA Gene knockdown Kidney 030102 biochemistry & molecular biology Chemistry Acute kidney injury nutritional and metabolic diseases Molecular Bases of Disease Drug Synergism Cell Biology Acute Kidney Injury medicine.disease Mice Inbred C57BL Meclofenamic acid 030104 developmental biology Endocrinology medicine.anatomical_structure Adipose Tissue Gene Expression Regulation Gene Knockdown Techniques RNA Tumor Suppressor Protein p53 medicine.drug |
| Zdroj: | J Biol Chem |
| ISSN: | 0021-9258 |
| Popis: | The role of RNA methylation on the sixth N atom of adenylate (m(6)A) in acute kidney injury (AKI) is unknown. FTO (fat mass and obesity-associated protein) reverses the m(6)A modification in cisplatin-induced AKI. Here, we aimed to determine FTO's role in AKI. We induced AKI in c57BL/6 mice by intraperitoneal cisplatin injection and treated the animal with vehicle or an FTO inhibitor meclofenamic acid (MA) for 3 days. Moreover, as an in vitro model, human kidney proximal tubular cells (HK2 cells) were treated with cisplatin. We found that the cisplatin treatment reduces FTO expression and increases m(6)A levels in vivo and in vitro. MA aggravated renal damage and increased apoptosis in cisplatin-treated kidneys, phenotypes that were correlated with reduced FTO expression and increased m(6)A levels. Moreover, MA promoted apoptosis in cisplatin-treated HK2 cells, which was correlated with the reduced FTO expression and increased m(6)A in HK2 cells. FTO protein overexpression reduced m(6)A levels and inhibited apoptosis in cisplatin-treated HK2 cells and also blocked the MA-induced increase in m(6)A levels and apoptosis rates. In agreement, overexpression of the m(6)A-generating methyltransferase-like 3 and 14 (METTL3 and METTL14) or siRNA-mediated FTO knockdown promoted apoptosis and enhanced m(6)A levels in cisplatin-treated HK2 cells. MA increased p53 mRNA and protein levels in AKI both in vitro and in vivo, and FTO overexpression reduced p53 expression and reversed the MA-induced p53 increase in AKI. In conclusion, reduced renal FTO expression in cisplatin-induced AKI increases RNA m(6)A levels and aggravates renal damages. |
| Databáze: | OpenAIRE |
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