MiR-21-5p in macrophage-derived extracellular vesicles affects podocyte pyroptosis in diabetic nephropathy by regulating
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ORIGINAL ARTICLE
MiR‑21‑5p in macrophage‑derived extracellular vesicles affects podocyte pyroptosis in diabetic nephropathy by regulating A20 X. Ding1 · N. Jing1 · A. Shen1 · F. Guo1 · Y. Song1 · M. Pan1 · X. Ma1 · L. Zhao1 · H. Zhang1 · L. Wu1 · G. Qin1 · Y. Zhao1 Received: 19 March 2020 / Accepted: 19 August 2020 © Italian Society of Endocrinology (SIE) 2020
Abstract 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. Keywords Diabetic nephropathy · Extracellular vesicles · Podocyte · Macrophage · miR-21-5p · A20
Introduction The incidence of diabetes has gradually elevated in recent years, and 40% of diabetic patients may have microvascular complications, namely diabetic nephropathy (DN), which is one of the most serious consequences of diabetes [1]. DN is the most common cause of end-stage renal disease, which is associated with a significantly elevated risk of cardiovascular disease and premature death [2]. The inflammatory response plays a central role in the progression of DN, and podocytes injury, which is the initial hallmark of DN plays Xiaoxu Ding and Na Jing contributed equally to this work and should be regarded as co-first authors. * Y. Zhao [email protected] 1
Department 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
an important role in inflammation-mediated DN [3, 4]. Classical activation of macrophages has pro-inflammatory effects and is a key process to aggravate renal damage [5]. It has been proven that macrophage-
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