Objective: To investigate the protective effects of gypenoside XVII (GP-17) against cisplatin-induced acute kidney injury and to elucidate whether its mechanism involves the activation of PINK1/Parkin-mediated mitophagy. Methods: Sprague-Dawley rats were randomly divided into four groups: control, cisplatin, cisplatin + GP-17, and GP-17 alone. Cisplatin was administered intraperitoneally at 20 mg/kg to induce acute kidney injury, while GP-17 was given orally at 40 mg/kg/ day for 7 d. The levels of serum creatinine and blood urea nitrogen, superoxide dismutase activity, and malondialdehyde content were measured. Histopathological analysis and transmission electron microscopy were also performed to evaluate the effects of GP-17 on renal injury. Moreover, the expression of mitophagy-related proteins, including PINK1, Parkin, LC3, and p62, and the mRNA expression of inflammatory markers were determined by Western blot and quantitative RT-PCR assays. Furthermore, human renal tubular epithelial HK-2 cells were treated with cisplatin and GP-17, with or without PINK1 siRNA transfection. Cell viability, apoptosis, reactive oxygen species levels, mitochondrial membrane potential, and the protein expression associated with the PINK1/Parkin pathway were measured. Results: In rats with cisplatin-induced acute kidney injury, GP-17 significantly ameliorated cisplatin-induced elevations in serum creatinine and blood urea nitrogen, attenuated tubular damage and mitochondrial ultrastructural injury, and reduced oxidative stress by increasing superoxide dismutase activity and decreasing malondialdehyde content. GP-17 further upregulated the protein levels of PINK1, Parkin, and LC3-II / I ratio while promoting p62 degradation, indicating enhanced mitophagic flux. In HK-2 cells, GP-17 (20 μM) co-treatment markedly attenuated cisplatin-induced cytotoxicity, apoptosis, reactive oxygen species overproduction, and mitochondrial depolarization. However, all these protective effects of GP-17 were completely abolished upon PINK1 knockdown. Conclusions: GP-17 protects against cisplatin-induced nephrotoxicity by activating PINK1/Parkin-mediated mitophagy, which facilitates the clearance of damaged mitochondria, alleviates oxidative stress, and inhibits renal cell apoptosis. These findings identify GP-17 as a promising candidate for mitigating chemotherapy-induced acute kidney injury.
LIN et al. (Sun,) studied this question.