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MiR-21-5p in macrophage-derived extracellular vesicles affects podocyte pyroptosis in diabetic nephropathy by
1Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou City, 450052, Henan, People's Republic of China.
Objectives:
Podocyte pyroptosis, characterized by inflammasome activation, plays an important role in inflammation-mediated diabetic nephropathy (DN). Our study aimed to investigate whether miR-21-5p in macrophage-derived extracellular vesicles (EVs) could affect podocyte injury in DN.
Methods:
EVs were extracted after the treatment of RAW 264.7 (mouse macrophage line) with high glucose (HG). The podocyte pyroptosis was determined using the flow cytometry and the western blot. After the knockdown of miR-21-5p in HG-induced RAW264.7 cells, we injected the extracted EVs into DN model mice.
Results:
The level of miR-21-5p was higher in HG-stimulated macrophage-derived EVs than in normal glucose-cultured macrophage-derived EVs. The co-culture of EVs and podocytes promoted reactive oxygen species (ROS) production and activation of inflammatory in MPC5 cells (mouse podocyte line). However, restraint of miR-21-5p in EVs reduced ROS production and inhibit inflammasome activation in MPC5 cells, thereby reducing podocytes injury. Meanwhile, we found that miR-21-5p inhibited the A20 expression through binding with its 3'-untranslated regions in MPC5 cells. Further studies showed that A20 was also involved in the regulation of miR-21-5p of RAW 264.7-derived EVs on MPC5 injury. At the same time, it was also proved in the DN model mice that miR-21-5p in macrophage-derived EVs could regulate podocyte injury.
Conclusion:
MiR-21-5p in macrophage-derived EVs can regulate pyroptosis-mediated podocyte injury by A20 in DN.
Insights
MicroRNA-21-5p within macrophage extracellular vesicles promotes podocyte injury in diabetic nephropathy by activating pyroptosis. Inhibiting miR-21-5p in these vesicles reduces inflammation and protects podocytes, offering a potential therapeutic target for DN.
Area of Science:
- Cell Biology
- Immunology
- Nephrology
Background:
- Diabetic nephropathy (DN) involves podocyte injury driven by inflammation and pyroptosis.
- Macrophage-derived extracellular vesicles (EVs) are implicated in the inflammatory processes of DN.
Purpose of the Study:
- To investigate the role of miR-21-5p in macrophage-derived EVs on podocyte injury in diabetic nephropathy.
- To elucidate the underlying mechanism involving inflammasome activation and A20 expression.
Main Methods:
- Macrophage cell lines (RAW 264.7) were stimulated with high glucose (HG) to produce EVs.
- EVs were analyzed for miR-21-5p levels, and co-cultured with podocytes (MPC5).
- DN model mice received EVs with manipulated miR-21-5p levels; podocyte pyroptosis was assessed via flow cytometry and Western blot.
Main Results:
- HG-stimulated macrophage EVs showed elevated miR-21-5p levels.
- These EVs promoted podocyte pyroptosis, increasing reactive oxygen species (ROS) and inflammasome activation.
- Knockdown of miR-21-5p in EVs attenuated these effects and reduced podocyte injury.
- MiR-21-5p was found to inhibit A20 expression, a key regulator in the pathway, in podocytes.
Conclusions:
- MiR-21-5p in macrophage-derived EVs exacerbates pyroptosis-mediated podocyte injury in DN.
- The mechanism involves the downregulation of A20 expression.
- Targeting miR-21-5p in EVs presents a potential therapeutic strategy for diabetic nephropathy.
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