Journal Article

Wogonin protects glomerular podocytes by targeting Bcl-2-mediated autophagy and apoptosis in diabetic kidney disease

Huang, Yue-bo, Li, Yuan-yuan, Zhu, Wei, Liu, Xue-qi, Meng, Xiao-ming, Hu, Xue-ru, Wu, Yong-gui, Qi, Xiang-ming, Jiang, Ling, Wang, Xian

2022

Overview

Diabetic kidney disease (DKD) is one of the microvascular complications of diabetes mellitus and a major cause of end-stage renal disease with limited treatment options. Wogonin is a flavonoid derived from the root of Scutellaria baicalensis Georgi, which has shown a potent renoprotective effect. But the mechanisms of action in DKD are not fully elucidated. In this study, we investigated the effects of wogonin on glomerular podocytes in DKD using mouse podocyte clone 5 (MPC5) cells and diabetic mice model. MPC5 cells were treated with high glucose (30 mM). We showed that wogonin (4, 8, 16 μM) dose-dependently alleviated high glucose (HG)-induced MPC5 cell damage, accompanied by increased expression of WT-1, nephrin, and podocin proteins, and decreased expression of TNF-α, MCP-1, IL-1β as well as phosphorylated p65. Furthermore, wogonin treatment significantly inhibited HG-induced apoptosis in MPC5 cells. Wogonin reversed HG-suppressed autophagy in MPC5 cells, evidenced by increased ATG7, LC3-II, and Beclin-1 protein, and decreased p62 protein. We demonstrated that wogonin directly bound to Bcl-2 in MPC5 cells. In HG-treated MPC5 cells, knockdown of Bcl-2 abolished the beneficial effects of wogonin, whereas overexpression of Bcl-2 mimicked the protective effects of wogonin. Interestingly, we found that the expression of Bcl-2 was significantly decreased in biopsy renal tissue of diabetic nephropathy patients. In vivo experiments were conducted in STZ-induced diabetic mice, which were administered wogonin (10, 20, 40 mg · kg −1  · d −1 , i.g.) every other day for 12 weeks. We showed that wogonin administration significantly alleviated albuminuria, histopathological lesions, and p65 NF-κB-mediated renal inflammatory response. Wogonin administration dose-dependently inhibited podocyte apoptosis and promoted podocyte autophagy in STZ-induced diabetic mice. This study for the first time demonstrates a novel action of wogonin in mitigating glomerulopathy and podocytes injury by regulating Bcl-2-mediated crosstalk between autophagy and apoptosis. Wogonin may be a potential therapeutic drug against DKD.

• Publisher: Springer Singapore,Nature Publishing Group
• Subject: Animals / Apoptosis / Apoptosis - drug effects / Autophagy / Autophagy - drug effects / Bcl-2 protein / Biomedical and Life Sciences / Biomedicine / Biopsy / Diabetes / Diabetes mellitus / Diabetic Nephropathies - drug therapy / Diabetic Nephropathies - metabolism / Diabetic Nephropathies - pathology / Diabetic nephropathy / Dose-Response Relationship, Drug / Drugs, Chinese Herbal - administration & dosage / Drugs, Chinese Herbal - pharmacology / End-stage renal disease / Flavanones - administration & dosage / Flavanones - pharmacology / Flavonoids / IL-1β / Immunology / Inflammation / Injections, Intraperitoneal / Internal Medicine / Kidney diseases / Kidney Glomerulus - drug effects / Kidney Glomerulus - metabolism / Male / Medical Microbiology / Mice / Mice, Inbred C57BL / Microvasculature / Molecular Structure / Monocyte chemoattractant protein 1 / Nephropathy / NF-κB protein / p62 Protein / Pharmacology/Toxicology / Podocytes - drug effects / Podocytes - metabolism / Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors / Proto-Oncogene Proteins c-bcl-2 - metabolism / Structure-Activity Relationship / Tumor necrosis factor-α / Vaccine