期刊
ANTIOXIDANTS & REDOX SIGNALING
卷 36, 期 10-12, 页码 740-759出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2021.0063
关键词
diabetic nephropathy; podocyte; mmu_circRNA_0000309; germacrone; miR-188-3p; GPX4; mitochondria damage
资金
- Construction of Key Projects by Zhejiang Provincial Ministry [WKJ-ZJ-1915, WKJ-ZJ-2017]
- Zhejiang Province Chinese Medicine Modernization Program [2020ZX001]
- General Project of Zhejiang Education Department [Y201942823]
- Construction Fund of Medical Key Disciplines of Hangzhou (2020-2024)
- Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project [2022ZB273]
- Clinical and Experimental Research of YSHS Granule
This study found that germacrone can improve kidney damage and inhibit podocyte apoptosis in diabetic nephropathy (DN) mice. Silencing mmu_circRNA_0000309 weakens the anti-apoptotic and anti-injury effects of germacrone, leading to aggravation of mitochondrial damage and ferroptosis. mmu_circRNA_0000309 competitively sponges miR-188-3p and subsequently promotes GPX4 expression, thereby deactivating ferroptosis-dependent mitochondrial damage and podocyte apoptosis.
Aims: Diabetic nephropathy (DN) is characterized by microalbuminuria, mainly associated with pathological and morphological alterations of podocyte. New drug targeting podocyte injury is a promising approach for treating DN. The present study is aimed at developing new drug targeting podocyte injury for treating DN. Results: In this study, germacrone ameliorated kidney damage and inhibited podocyte apoptosis in a DN mouse model. Based on RNA-seq, mmu_mmu_circRNA_0000309, located in host gene vascular endothelial zinc finger 1 (Vezf1), showed a sharp decline in DN mice and a remarkable recovery in germacrone-challenged DN mice. mmu_circRNA_0000309 silence or miR-188-3p mimics abrogated the antiapoptosis and anti-injury effects of germacrone through aggravating mitochondria damage, and elevating reactive oxygen species and ferroptosis-related protein levels. Mechanistically, mmu_circRNA_0000309 competitively sponged miR-188-3p, and subsequently promoted glutathione peroxidase 4 (GPX4) expression, thereby inactivating ferroptosis-dependent mitochondrial damage and podocyte apoptosis. In addition, GPX4 overexpression neutralized mmu_circRNA_0000309 silence-mediated mitochondria damage and ferroptosis in germacrone-exposed MPC5 cells. Innovation: We describe the novel effect and mechanism of germacrone on treating DN, which is linked to ferroptosis for the first time. Conclusion: mmu_circRNA_0000309 silence mediates drug resistance to germacrone in DN mice. mmu_circRNA_0000309 sponges miR-188-3p, and subsequently upregulates GPX4 expression, inactivating ferroptosis-dependent mitochondrial function and podocyte apoptosis. Possibly germacrone-based treatment for DN can be further motivated by regulating mmu_circRNA_0000309/miR-188-3p/GPX4 signaling axis. [GRAPHICS] .
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据