METTL3/YTHDF2 m6A axis mediates the progression of diabetic nephropathy through epigenetically suppressing PINK1 and mitophagy
| Autor: | Fangfang Wang, Juan Bai, Xin Zhang, Dali Wang, Jingwen Xue, Haoyang Chen, Shuxiang Wang, Baojin Chi, Jing Li, Xiaoru Ma |
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| Jazyk: | angličtina |
| Rok vydání: | 2024 |
| Předmět: | |
| Zdroj: | Journal of Diabetes Investigation, Vol 15, Iss 3, Pp 288-299 (2024) |
| Druh dokumentu: | article |
| ISSN: | 2040-1124 2040-1116 |
| DOI: | 10.1111/jdi.14113 |
| Popis: | ABSTRACT Aims This research aimed to investigate the specific mechanism of methyltransferase like 3 (METTL3) in the progression of diabetic kidney disease (DKD). Materials and Methods The model of diabetic kidney disease was established with HK‐2 cells and mice in vitro and in vivo. The N6 methyladenosine (m6A) contents in the cells and tissues were detected with a commercial kit and the m6A levels of PTEN induced putative kinase 1 (PINK2) were detected with a MeRIP kit. The mRNA and protein levels were determined with RT‐qPCR and western blot. The ROS, TNF‐α, and IL‐6 levels were assessed with ELISA. The cell proliferative ability was measured by a CCK‐8 assay and cell apoptosis was determined with TUNEL staining. The HE and Masson staining was performed to observe the renal morphology. The RIP assay was conducted to detect the interaction between METTL3/YTHDF2 and PINK1. Results The m6A content and METTL3 levels were prominently elevated in diabetic kidney disease. METTL3 silencing promoted the cell growth and the expression of LC3 II, PINK1, and Parkin, while inhibiting the cell apoptosis and the expression of LC3 I and p62 in the high glucose (HG) stimulated HK‐2 cells. METTL3 silencing also decreased the ROS, TNF‐α, and IL‐6 levels in diabetic kidney disease. PINK1 silencing neutralized the function of sh‐METTL3 in the HG stimulated HK‐2 cells. The HE and Masson staining showed that METTL3 silencing alleviated the kidney injury induced by DKD. METTL3 silencing decreased the m6A levels of PINK1, while increased the mRNA levels of PINK1 which depended on YTHDF2. Conclusions METTL3 silencing could inhibit the progression of diabetic nephropathy in vivo and in vitro by regulating the m6A modification of PINK1, which depends on YTHDF2. Our research lays the theoretical foundation for the precise treatment of diabetic kidney disease and the development of targeted drugs in the future. |
| Databáze: | Directory of Open Access Journals |
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