Gypenoside XVII protects against cisplatin-induced acute kidney injury by activating PINK1/Parkin-mediated mitophagy

Abstract

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.

Keywords

Gypenoside XVII / Acute kidney injury / Cisplatin / PINK1/Parkin signaling pathway / Mitophagy

Conflict of interest statement

The authors declare that they have no conflict of interest.

Funding

This study was supported by grants from the Health Commission of Zigong High-Level Talent Development Project (WJW-GCCRC007).

Data availability statement

The data supporting the findings of this study are available from the corresponding author upon request.

Authors’ contributions

LZL was responsible for conceptualization, methodology, investigation, formal analysis, writing original draft. JLW was involved in investigation, data curation, and validation. HWC contributed to resources, methodology, and formal analysis. YH was responsible for conceptualization, supervision, project administration, funding acquisition, as well as writing and editing the article. All authors reviewed and approved the final manuscript.

Publisher’s note

The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

[1] Tan Z, Guo F, Huang Z, Xia Q, Cao Z, Yang Y, et al. Pharmacological and genetic inhibition of fatty acid-binding protein 4 alleviated cisplatin-induced acute kidney injury. J Cell Mol Med 2019; 23(9): 6260-6270.

[2] Miao J, Zhu H, Wang J, Li M, Li R, Yuan F, et al. Experimental models for preclinical research in kidney disease. Zool Res 2024; 45(5): 1161-1174.

[3] Park CH, Lee B, Han M, Kim J, Kim H, Kim J, et al. Canagliflozin protects against cisplatin-induced acute kidney injury by AMPK-mediated autophagy in renal proximal tubular cells. Cell Death Discov 2022; 8(1). doi: 10.1038/s41420-021-00801-9.

[4] Lameire NH, Bagga A, Cruz D, De Maeseneer J, Endre Z, Kellum JA, et al. Acute kidney injury: An increasing global concern. Lancet 2013; 382(9887): 170-179.

[5] Lin Q, Li S, Jin H, Cai H, Yu J, Qi L, et al. Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis. Int J Biol Sci 2023; 19(4): 1192-1210.

[6] Tang C, Cai J, Yin XM, Weinberg JM, Venkatachalam MA, Dong Z. Mitochondrial quality control in kidney injury and repair. Nat Rev Nephrol 2021; 17(5): 299-318.

[7] Yoon YM, Go G, Yoon S, Lim JH, Lee G, Lee JH, et al. Melatonin treatment improves renal fibrosis via miR-4516/SIAH3/PINK 1 axis. Cells 2021; 10(7). doi: 10.3390/cells10071682.

[8] Anwer T, Alshahrani S, Somaili AMH, Alshehri BM, Khan AA, Alzahrani AR, et al. Nephroprotective effect of diosmin against cisplatin-induced kidney damage by modulating IL-1β IL-6, TNFα and renal oxidative damage. Molecules 2023; 28(3). doi: 10.3390/molecules28031302.

[9] Cao LH, Zhao YY, Bai M, Wu Y, Chen LW, Qiu F. Mechanistic studies of gypenosides in microglial state transition and its implications in depression-like behaviors: Role of TLR4/MyD88/NF-KB signaling. Front Pharmacol 2022; 13. doi: 10.3389/fphar.2022.838261.

[10] Alfwuaires M. Ursolic acid alleviates isoproterenol-induced kidney injury in mice by suppressing inflammation, apoptosis, and oxidative stress via the PI3K/Akt signaling. Asian Pac J Trop Biomed 2025; 15(8): 324-332.

[11] Sun T, Duan L, Li J, Guo X, Li S, Wu D, et al. Gypenoside XVII protects against spinal cord injury in mice by regulating the microRNA 21 mediated PTEN/AKT/mTOR pathway. Int J Mol Med 2021; 48(2): 149. doi: 10.3892/ijmm.2021.4979.

[12] Yu Y, Wang M, Chen R, Song Z, Li L, Li S, et al. Gypenoside XVII protects against myocardial ischemia and reperfusion injury by inhibiting ER stress-induced mitochondrial injury. J Ginseng Res 2021; 45(6): 642653.

[13] Xie W, Zhu T, Zhang S, Xu L, Zhang L, Xu J, et al. Protective effects of Gypenoside XVII against cerebral ischemia/reperfusion injury via SIRT1-FOXO3A- and Hif1a-BNIP3-mediated mitochondrial autophagy. J Transl Med 2022; 20(1): 622. doi: 10.1186/s12967-022-03830-9.

[14] Meng X, Wang M, Sun G, Ye J, Zhou Y, Dong X, et al. Attenuation of Aβ25-35-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways. Toxicol Appl Pharmacol 2014; 279(1): 63-75.

[15] Meng X, Luo Y, Liang T, Wang S, Liu H, Wang S, et al. Gypenoside XVII enhances lysosome biogenesis and autophagy flux and accelerates autophagic clearance of amyloid-β through TFEB activation. J Alzheimers Dis 2016; 52(3): 1135-1150.

[16] Wang J, Yu Y, Zhang H, Li S, Chen R, Hao Y. Gypenoside XVII attenuates renal ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress and NLRP3 inflammasome-triggered pyroptosis. Eur J Pharmacol 2024; 962. doi: 10.1016/j.ejphar.2023.176187.

[17] Li Z, He R, Liu J, Chen Y, Li P, Li X, et al. JianPiYiShen formula prevents cisplatin-induced acute kidney injury in mice by improving necroptosis through MAPK pathway. BMC Complement Med Ther 2024; 24(1). doi: 10.1186/s12906-024-04366-9.

[18] Zeng X, Zhou X, Zhou J, Zhou H, Hong X, Li D, et al. Limonin mitigates cisplatin-induced acute kidney injury through metabolic reprogramming. Biomed Pharmacother 2023; 167. doi: 10.1016/j.biopha.2023.115531.

[19] Zhang Z, Chen H, Zhou L, Li C, Lu G, Wang L. Macrophage-derived exosomal miRNA-155 promotes tubular injury in ischemia-induced acute kidney injury. Int J Mol Med 2022; 50(3). doi: 10.3892/ijmm.2022.5172.

[20] Pabla N, Dong Z. Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies. Kidney Int 2008; 73(9): 994-1007.

[21] Khan MM, Madni A, Torchilin V, Filipczak N, Pan J, Tahir N, et al. Lipid-chitosan hybrid nanoparticles for controlled delivery of cisplatin. Drug Deliv 2019; 26(1): 765-772.

[22] Tang L, Li X, Qin Y, Liu X, Zhang X, Wang X, et al. The construction of oligonucleotide-cycloastragenol and the renoprotective effect study. Front Bioeng Biotechnol 2022; 10. doi: 10.3389/fbioe.2022.1027517.

[23] Yu P, Gu T, Rao Y, Liang W, Zhang X, Jiang H, et al. A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization. Acta Pharm Sin B 2024; 14(7): 3250-3232.

[24] Qiao Y, Xu L, Tao X, Yin L, Qi Y, Xu Y, et al. Protective effects of dioscin against fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress, fibrosis, lipid metabolism and inflammation. Toxicol Lett 2018; 284: 37-45.

[25] Hadian K, Stockwell BR. The therapeutic potential of targeting regulated non-apoptotic cell death. Nat Rev Drug Discov 2023; 22(9): 723-742.

[26] Yuan L, Yuan Y, Liu F, Zhou L, Su J, Li X, et al.PGC-1α alleviates mitochondrial dysfunction via TFEB-mediated autophagy in cisplatin-induced acute kidney injury. Aging (Albany NY) 2021; 13(6): 8421-8439.

[27] Yao C, Li Z, Sun K, Zhang Y, Shou S, Jin H. Mitochondrial dysfunction in acute kidney injury. Ren Fail 2024; 46(2). doi: 10.1080/0886022X.2024.2393262.

[28] Brier LW, Ge L, Stjepanovic G, Thelen AM, Hurley JH, Schekman R. Regulation of LC 3 lipidation by the autophagy-specific class III phosphatidylinositol-3 kinase complex. Mol Biol Cell 2019; 30(9): 1098-1107.

[29] Sears SM, Dupre TV, Shah PP, Davis DL, Doll MA, Sharp CN, et al. Neutral ceramidase deficiency protects against cisplatin-induced acute kidney injury. J Lipid Res 2022; 63(3). doi: 10.1016/j.jlr.2022.100179.

[30] Tang S, Geng Y, Lin Q. The role of mitophagy in metabolic diseases and its exercise intervention. Front Physiol 2024; 15. doi: 10.3389/fphys.2024.1339128.