Diosgenin Inhibits ROS Generation by Modulating NOX4 and Mitochondrial Respiratory Chain and Suppresses Apoptosis in Diabetic Nephropathy

• Published in: Nutrients 2023-04, Vol.15 (9), p.2164
• Main Authors: Zhong, Yujie, Wang, Lei, Jin, Ruyi, Liu, Jiayu, Luo, Ruilin, Zhang, Yinghan, Zhu, Lin, Peng, Xiaoli
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Apaf-1 protein; Apoptosis; Apoptosis - drug effects; Caspase-12; Caspase-3; Caspase-9; Cell culture; Cell Line; Cell Respiration - drug effects; Cell viability; Diabetes; Diabetes mellitus; Diabetic nephropathies; Diabetic nephropathy; Diabetic Neuropathies - metabolism; Diabetics; diosgenin; Diosgenin - pharmacology; Electron transport chain; Endoplasmic Reticulum Stress; Enzymes; ER stress; Glucose; High fat diet; Humans; Hydrogen peroxide; Hyperglycemia; Kidneys; Male; Membrane potential; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial DNA; Nephropathy; NOX4; NOX4 protein; Oxidative stress; Progesterone; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Remission; Streptozocin
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu15092164

Diosgenin (DIO) is a dietary steroid sapogenin possessing multiple biological functions, such as the amelioration of diabetes. However, the remission effect of DIO on diabetic nephropathy (DN) underlying oxidative stress and cell apoptosis remains unclear. Here, the effect of DIO on ROS generation and its induced cell apoptosis was studied in vitro and in vivo. Renal proximal tubular epithelial (HK-2) cells were treated with DIO (1, 2, 4 µM) under high glucose (HG, 30 mM) conditions. DN rats were induced by a high-fat diet combined with streptozotocin, followed by administration of DIO for 8 weeks. Our data suggested that DIO relieved the decline of HK-2 cell viability and renal pathological damage in DN rats. DIO also relieved ROS (O and H O ) production. Mechanistically, DIO inhibited the expression of NOX4 and restored mitochondrial respiratory chain (MRC) complex I-V expressions. Further, DIO inhibited mitochondrial apoptosis by ameliorating mitochondrial membrane potential (MtMP) and down-regulating the expressions of CytC, Apaf-1, caspase 3, and caspase 9, while up-regulating Bcl2 expression. Moreover, the ER stress and its associated cell apoptosis were inhibited through decreasing PERK, -PERK, ATF4, IRE1, -CHOP, and caspase 12 expressions. Collectively, DIO inhibited ROS production by modulating NOX4 and MRC complexes, which then suppressed apoptosis regulated by mitochondria and ER stress, thereby attenuating DN.