BACKGROUND: Diabetic nephropathy (DN) is a common complication of diabetes, characterized by high prevalence and mortality rates. Tubular damage is a significant pathological aspect of DN. Mitophagy plays a crucial role in tubular damage associated with DN. Swietenine (Swi) is the main bioactive compound isolated and purified from the fruits of S. macrophylla, and it has been shown to have anti-inflammatory, antioxidant, and anti-diabetic activities. Previous studies have indicated that Swi provides strong kidney protection in DN, but the underlying mechanisms by which Swi influences DN remain unclear.
OBJECTIVE: This study aims to clarify the renal protective effects of Swi during the development of DN and explore its potential molecular mechanisms.
METHODS: This study used high-fat diet and streptozotocin (HFD/STZ)-induced DN mice as an in vivo model, and human renal tubular epithelial cells (HK-2 cells) treated with high glucose combined with palmitic acid (HG/PA) as an in vitro model. After 8 weeks of treatment with Swi, serum and urine levels of renal function-related indicators were measured. Renal tissue sections were subjected to histopathological staining, and changes in mitochondrial morphology and number were observed using transmission electron microscopy (TEM). Levels of proteins associated with oxidative stress, apoptosis, autophagy, and mitophagy-related proteins were measured through via Western blotting (WB), immunofluorescence (IF) staining, flow cytometry, and fluorescent probes. Proteomics results based on tandem mass tag (TMT) were used to explore the potential mechanisms of Swi in DN. Finally, siRNA transfection was used to reveal the role of the Acsf2/PHB2/PINK1 pathway in HK-2 cells treated with HG and PA.
RESULTS: Swi improved renal function in diabetic mice and alleviated insulin resistance, oxidative stress, and apoptosis levels in DN mice. Swi alleviated tubular injury and enhanced mitophagy levels in both in vivo and in vitro models. Additionally, Swi reduced mitochondrial reactive oxygen species (ROS) production and restored mitochondrial function. Importantly, the protective effects of Swi on HG/PA-induced HK-2 cells was abolished after siRNA transfection and the use of the mitophagy inhibitor Mdivi-1, further confirming that Swi alleviates diabetic kidney tubular injury by activating the Acsf2/PHB2/PINK1 signaling pathway.
CONCLUSION: Swi enhances mitophagy through the Acsf2/PHB2/PINK1 pathway to alleviate diabetic kidney tubular damage. This study provides new evidence that Swi could be a potential drug for preventing and treating DN.
