Dapagliflozin prevents renal injury by improving mitochondrial function and reducing oxidative stress in diabetes patients: Study

Researchers found that dapagliflozin, an SGLT2 inhibitor, effectively improved mitochondrial function and reduced oxidative stress in palmitate-induced renal tubular epithelial cells, offering promising insights into its therapeutic application for diabetic nephropathy.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, widely used in managing diabetic nephropathy, have shown protective effects extending beyond glucose regulation, including organ preservation. One of their key benefits lies in mitigating mitochondrial dysfunction and oxidative stress, major contributors to diabetic kidney disease and its progression to renal injury.

Against the above background, Tingting Ding, Department of Endocrinology, Xuancheng People's Hospital, Xuancheng, Anhui Province, China, and colleagues explored the protective role of the SGLT2 inhibitor, dapagliflozin, in preventing palmitate-induced injury in renal tubular epithelial cells (HK-2), with a specific focus on mitochondrial function and oxidative stress. HK-2 cells were exposed to 150 μmol/L palmitate to trigger mitochondrial dysfunction and oxidative stress, followed by co-treatment with 2 μmol/L DAPA for 24 hours.

The study led to the following findings:

• DAPA significantly enhanced cell viability while reducing reactive oxygen species (ROS) levels.
• Mitochondrial membrane potential was restored following DAPA treatment.
• Malondialdehyde (MDA) levels were notably reduced, whereas superoxide dismutase (SOD) expression was significantly increased.
• Western blot analysis showed that DAPA reversed palmitate-induced upregulation of apoptosis-related proteins, including Bax and Cytochrome C.
• DAPA mitigated the overactivation of autophagy-related proteins, such as LC3 and Beclin-1, suggesting its role in modulating autophagy in diabetic nephropathy.
• Electron microscopy revealed improved mitochondrial morphology, reduced swelling, and restored cristae structure.

These findings highlight the dual role of DAPA in improving mitochondrial function and maintaining a balance between oxidative stress and autophagy, thereby protecting against kidney damage. However, the researchers note that the study's reliance on an in vitro model presents a limitation, as HK-2 cell experiments cannot fully replicate the physiological complexity of the human body. Consequently, further validation is needed to confirm the clinical relevance of these findings. Additionally, the study did not comprehensively assess the dose-response relationship of DAPA, leaving gaps in understanding its protective mechanisms at varying concentrations.

"Future research will focus on in vivo studies using animal models and clinical trials to establish DAPA’s role in mitigating mitochondrial damage, regulating oxidative stress, and modulating autophagy. Investigating its potential in combination therapies and evaluating its efficacy at different stages of chronic kidney disease will also be crucial in refining treatment strategies for diabetic nephropathy," the researchers concluded.

Reference:

Ding, T., Song, M., Wang, S., Huang, C., & Pan, T. (2025). Dapagliflozin has protective effects on palmitate-induced renal tubular epithelial cells by enhancing mitochondrial function and reducing oxidative stress. Journal of Diabetes and its Complications, 39(2), 108930. https://doi.org/10.1016/j.jdiacomp.2024.108930