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Diabetic nephropathy (DN) is a worldwide health problem with increasing incidence. Diosgenin (DIO) is a natural active ingredient extracted from Chinese yams (Rhizoma dioscoreae) with potential antioxidant, anti-inflammatory, and antidiabetic effects. However, the protective effect of DIO on DN is still unclear. The present study explored the mitigating effects and underlying mechanisms of DIO on DN in vivo and in vitro. In the current study, the DN rats were induced by a high-fat diet and streptozotocin and then treated with DIO and metformin (Mef, a positive control) for 8 weeks. The high-glucose (HG)-induced HK-2 cells were treated with DIO for 24 h. The results showed that DIO decreased blood glucose, biomarkers of renal damage, and renal pathological changes with an effect comparable to that of Mef, indicating that DIO is potential active substance to relieve DN. Thus, the protective mechanism of DIO on DN was further explored. Mechanistically, DIO improved autophagy and mitophagy via the regulation of the AMPK-mTOR and PINK1-MFN2-Parkin pathways, respectively. Knockdown of CaMKK2 abolished AMPK-mTOR and PINK1-MFN2-Parkin pathways-mediated autophagy and mitophagy. Mitophagy and mitochondrial dynamics are closely linked physiological processes. DIO also improved mitochondrial dynamics through inhibiting fission-associated proteins (DRP1 and p-DRP1) and increasing fusion proteins (MFN1/2 and OPA1). The effects were abolished by CaMKK2 and PINK1 knockdown. In conclusion, DIO ameliorated DN by enhancing autophagy and mitophagy and by improving mitochondrial dynamics in a CaMKK2-dependent manner. PINK1 and MFN2 are proteins that concurrently regulated mitophagy and mitochondrial dynamics. [ABSTRACT FROM AUTHOR]

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 (O2− and H2O2) 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, p-PERK, ATF4, IRE1, p-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. [ABSTRACT FROM AUTHOR]

Jujuboside A (JuA) is a triterpenoid saponins isolated from the seed of jujube (semen Ziziphi spinosae) with anti-oxidant, anti-inflammation and anti-apoptosis properties. The present study aimed to investigate the reno-protective effects of JuA on type II diabetes. JuA (20 mg/kg) and Metformin (Met, 300 mg/kg) were administrated to diabetic Sprague Dawley rat for 8 weeks daily. Our results showed that JuA reduced blood glucose and kidney function markers including 24 h urinary protein, urinary β-NAG/urinary creatinine, serum urea nitrogen, serum uric acid and serum creatinine, and relieved renal pathological changes. In addition, JuA decreased O 2 − and H 2 O 2 level, enhanced SOD, CAT and GPx activities, decreased NOX4 expression and improved mitochondrial respiratory chain function through regulating respiratory chain complex expression. Moreover, JuA downregulated the expressions of mitochondrial apoptosis proteins: Bax, CytC, Apaf-1 and caspase 9. Apoptosis mediated by ER stress also been inhibited by JuA via downregulating p-PERK, p-IRE1, XBP1s, ATF4, p-CHOP and caspase 12 expressions. JuA also enhanced autophagy and mitophagy via regulating CaMKK2-AMPK-p-mTOR and PINK1/Parkin pathways. Collectively, these results indicated that JuA protected against type II diabetic nephropathy through inhibiting oxidative stress and apoptosis mediated by mitochondria and ER stress. In addition, autophagy and mitophagy was enhanced by JuA. [Display omitted] • Jujuboside A relieved oxidative stress through inhibiting NOX4 and improving mitochondrial respiratory chain function in DN rat. • Jujuboside A enhanced antioxidant enzyme activities in DN rat. • Jujuboside A inhibited apoptosis induced by ER stress and mitochondria in DN rat. • Autophagy and mitophagy contributed to the protective effect of Jujuboside A on DN rat. [ABSTRACT FROM AUTHOR]