Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Kaempferide ameliorates cisplatin-induced nephrotoxicity via inhibiting oxidative stress and inducing autophagy

Acta Pharmacologica Sinica volume 44, pages 1442–1454 (2023)Cite this article

Abstract

Acute kidney injury (AKI) caused by anti-tumor drugs, such as cisplatin, is a severe complication with no effective treatment currently, leading to the reduction or discontinuation of chemotherapy. Natural products or herbal medicines are gradually considered as promising agents against cisplatin-induced AKI with the advantages of multi-targeting, multi-effects, and less resistance. In this study, we investigated the effects of kaempferide, a natural flavonoid extracted from the rhizome of Kaempferia galanga, in experimental AKI models in vitro and in vivo. We first conducted pharmacokinetic study in mice and found a relative stable state of kaempferide with a small amount of conversion into kaempferol. We showed that both kaempferide (10 μM) and kaempferol (10 μM) significantly inhibited cisplatin-caused injuries in immortalized proximal tubule epithelial cell line HK-2. In AKI mice induced by injection of a single dose of cisplatin (15 mg/kg), oral administration of kaempferide (50 mg/kg) either before or after cisplatin injection markedly improved renal function, and ameliorated renal tissue damage. We demonstrated that kaempferide inhibited oxidative stress and induced autophagy in cisplatin-treated mice and HK-2 cells, thus increasing tubular cell viability and decreasing immune responses to attenuate the disease progression. In addition, treatment with kaempferide significantly ameliorated ischemia-reperfusion-induced renal injury in vitro and in vivo. We conclude that kaempferide is a promising natural product for treating various AKI. This study has great implications for promotion of its use in healthcare products, and help to break through the limited use of cisplatin in the clinic.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pharmacokinetic study of kaempferide and its protection in HK-2 cell toxicity.
Fig. 2: Kaempferide prevents the nephrotoxicity caused by cisplatin.
Fig. 3: Kaempferide treatment attenuates cisplatin-induced AKI.
Fig. 4: The immune response is reduced in kaempferide-treated cis-AKI mice.
Fig. 5: Cisplatin-induced oxidative stress is inhibited after kaempferide treatment.
Fig. 6: Autophagy is induced after kaempferide treatment in HK-2 cells.
Fig. 7: Autophagy induction is required in the renal protection of kaempferide.
Fig. 8: Kaempferide treatment attenuates ischemia-reperfusion-induced AKI.
Fig. 9: Schematic diagram of kaempferide’s protection against acute kidney injury.

Similar content being viewed by others

References

  1. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Stehlik J, Armstrong B, Baran DA, Bridges ND, Chandraker A, Gordon R, et al. Early immune biomarkers and intermediate-term outcomes after heart transplantation: Results of Clinical Trials in Organ Transplantation-18. Am J Transpl. 2019;19:1518–28.

    Article  CAS  Google Scholar 

  3. Pierson Marchandise M, Gras V, Moragny J, Micallef J, Gaboriau L, Picard S, et al. The drugs that mostly frequently induce acute kidney injury: a case - noncase study of a pharmacovigilance database. Br J Clin Pharmacol. 2017;83:1341–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Beyer J, Rick O, Weinknecht S, Kingreen D, Lenz K, Siegert W. Nephrotoxicity after high-dose carboplatin, etoposide and ifosfamide in germ-cell tumors: incidence and implications for hematologic recovery and clinical outcome. Bone Marrow Transpl. 1997;20:813–9.

    Article  CAS  Google Scholar 

  5. Winston JA, Safirstein R. Reduced renal blood flow in early cisplatin-induced acute renal failure in the rat. Am J Physiol. 1985;249:F490–6.

    CAS  PubMed  Google Scholar 

  6. Bonventre JV, Zuk A. Ischemic acute renal failure: an inflammatory disease? Kidney Int. 2004;66:480–5.

    Article  CAS  PubMed  Google Scholar 

  7. Yang YW, Yu XW, Zhang Y, Ding GX, Zhu CH, Huang SM, et al. Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury. Clin Sci. 2018;132:825–38.

    Article  CAS  Google Scholar 

  8. Prasad SB, Rosangkima G, Kharbangar A. Structural and biochemical changes in mitochondria after cisplatin treatment of Dalton’s lymphoma-bearing mice. Mitochondrion. 2010;10:38–45.

    Article  CAS  PubMed  Google Scholar 

  9. Salei N, Rambichler S, Salvermoser J, Papaioannou NE, Schuchert R, Pakalniskyte D, et al. The kidney contains ontogenetically distinct dendritic cell and macrophage subtypes throughout development that differ in their inflammatory properties. J Am Soc Nephrol. 2020;31:257–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yang C, Kaushal V, Shah SV, Kaushal GP. Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells. Am J Physiol Ren Physiol. 2008;294:F777–87.

    Article  CAS  Google Scholar 

  11. Jiang M, Wei Q, Dong G, Komatsu M, Su Y, Dong Z. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 2012;82:1271–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang Y, Tang C, Cai J, Chen G, Zhang D, Zhang Z, et al. PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity to protect against kidney injury. Cell Death Dis. 2018;9:1113.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ridzuan NRA, Rashid NA, Othman F, Budin SB, Hussan F, Teoh SL. Protective role of natural products in cisplatin-induced nephrotoxicity. Mini Rev Med Chem. 2019;19:1134–43.

    Article  PubMed  Google Scholar 

  14. Fang CY, Lou DY, Zhou LQ, Wang JC, Yang B, He QJ, et al. Natural products: potential treatments for cisplatin-induced nephrotoxicity. Acta Pharmacol Sin. 2021;42:1951–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yue ME, Jiang TF, Shi YP. Fast determination of flavonoids in Hippophae rhamnoides and its medicinal preparation by capillary zone electrophoresis using dimethyl-beta-cyclodextrin as modifier. Talanta. 2004;62:695–9.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang Q, Cui H. Simultaneous determination of quercetin, kaempferol, and isorhamnetin in phytopharmaceuticals of Hippophae rhamnoides L. by high-performance liquid chromatography with chemiluminescence detection. J Sep Sci. 2005;28:1171–8.

    Article  CAS  PubMed  Google Scholar 

  17. Pundir S, Garg P, Dviwedi A, Ali A, Kapoor VK, Kapoor D, et al. Ethnomedicinal uses, phytochemistry and dermatological effects of Hippophae rhamnoides L.: a review. J Ethnopharmacol. 2021;266:113434.

    Article  CAS  PubMed  Google Scholar 

  18. Yamaga M, Tani H, Nishikawa M, Fukaya K, Ikushiro SI, Murota K. Pharmacokinetics and metabolism of cinnamic acid derivatives and flavonoids after oral administration of Brazilian green propolis in humans. Food Funct. 2021;12:2520–30.

    Article  CAS  PubMed  Google Scholar 

  19. Otake Y, Walle T. Oxidation of the flavonoids galangin and kaempferide by human liver microsomes and CYP1A1, CYP1A2, and CYP2C9. Drug Metab Dispos. 2002;30:103–5.

    Article  PubMed  Google Scholar 

  20. Jiang ZT, Wang JC, Chen XF, Wang X, Wang TF, Zhu ZT, et al. Simultaneous determination of kaempferide, kaempferol and isorhamnetin in rat plasma by ultra-high performance liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. J Braz Chem Soc. 2018;29:535–42.

    CAS  Google Scholar 

  21. Tie F, Ding J, Hu N, Dong Q, Chen Z, Wang H. Kaempferol and kaempferide attenuate oleic acid-induced lipid accumulation and oxidative stress in HepG2 cells. Int J Mol Sci. 2021;22:8847.

  22. Srinivasan E, Rajasekaran R. Comparative binding of kaempferol and kaempferide on inhibiting the aggregate formation of mutant (G85R) SOD1 protein in familial amyotrophic lateral sclerosis: a quantum chemical and molecular mechanics study. Biofactors. 2018;44:431–42.

    Article  CAS  PubMed  Google Scholar 

  23. Weng Q, Sun H, Fang C, Xia F, Liao H, Lee J, et al. Catalytic activity tunable ceria nanoparticles prevent chemotherapy-induced acute kidney injury without interference with chemotherapeutics. Nat Commun. 2021;12:1436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bejoy J, Qian ES, Woodard LE. Tissue culture models of AKI: from tubule cells to human kidney organoids. J Am Soc Nephrol. 2022;33:487–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tanase DM, Gosav EM, Radu S, Costea CF, Ciocoiu M, Carauleanu A, et al. The predictive role of the biomarker kidney molecule-1 (KIM-1) in acute kidney injury (AKI) cisplatin-induced nephrotoxicity. Int J Mol Sci. 2019;20:5238.

  26. Martensson J, Bellomo R. The rise and fall of NGAL in acute kidney injury. Blood Purif. 2014;37:304–10.

    Article  CAS  PubMed  Google Scholar 

  27. Niedernhofer LJ, Daniels JS, Rouzer CA, Greene RE, Marnett LJ. Malondialdehyde, a product of lipid peroxidation, is mutagenic in human cells. J Biol Chem. 2003;278:31426–33.

    Article  CAS  PubMed  Google Scholar 

  28. Kim D, Hwang HY, Kwon HJ. A natural small molecule induces MAPT clearance via mTOR-independent autophagy. Biochem Biophys Res Commun. 2021;568:30–6.

    Article  CAS  PubMed  Google Scholar 

  29. Kim D, Hwang HY, Ji ES, Kim JY, Yoo JS, Kwon HJ. Activation of mitochondrial TUFM ameliorates metabolic dysregulation through coordinating autophagy induction. Commun Biol. 2021;4:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang Y, Liu Z, Shu S, Cai J, Tang C, Dong Z. AMPK/mTOR signaling in autophagy regulation during cisplatin-induced acute kidney injury. Front Physiol. 2020;11:619730.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhao Y, Feng X, Li B, Sha J, Wang C, Yang T, et al. Dexmedetomidine protects against lipopolysaccharide-induced acute kidney injury by enhancing autophagy through inhibition of the PI3K/AKT/mTOR pathway. Front Pharmacol. 2020;11:128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu L, Yuan Y, Yuan L, Li L, Liu F, Liu J, et al. Activation of TFEB-mediated autophagy by trehalose attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury. Theranostics. 2020;10:5829–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tang C, Livingston MJ, Liu Z, Dong Z. Autophagy in kidney homeostasis and disease. Nat Rev Nephrol. 2020;16:489–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wu YT, Tan HL, Shui G, Bauvy C, Huang Q, Wenk MR, et al. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem. 2010;285:10850–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kanagasundaram NS. Pathophysiology of ischaemic acute kidney injury. Ann Clin Biochem. 2015;52:193–205.

    Article  CAS  PubMed  Google Scholar 

  36. Rao Y, Wan Q, Su H, Xiao X, Liao Z, Ji J, et al. ROS-induced HSP70 promotes cytoplasmic translocation of high-mobility group box 1b and stimulates antiviral autophagy in grass carp kidney cells. J Biol Chem. 2018;293:17387–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Su Y, Lu J, Gong P, Chen X, Liang C, Zhang J. Rapamycin induces autophagy to alleviate acute kidney injury following cerebral ischemia and reperfusion via the mTORC1/ATG13/ULK1 signaling pathway. Mol Med Rep. 2018;18:5445–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yuan P, Sun X, Liu X, Hutterer G, Pummer K, Hager B, et al. Kaempferol alleviates calcium oxalate crystal-induced renal injury and crystal deposition via regulation of the AR/NOX2 signaling pathway. Phytomedicine. 2021;86:153555.

    Article  CAS  PubMed  Google Scholar 

  39. Ji X, Cao J, Zhang L, Zhang Z, Shuai W, Yin W. Kaempferol protects renal fibrosis through activating the BMP-7-Smad1/5 signaling pathway. Biol Pharm Bull. 2020;43:533–9.

    Article  CAS  PubMed  Google Scholar 

  40. Alshehri AS. Kaempferol attenuates diabetic nephropathy in streptozotocin-induced diabetic rats by a hypoglycaemic effect and concomitant activation of the Nrf-2/Ho-1/antioxidants axis. Arch Physiol Biochem. 2021:1–14. https://doi.org/10.1080/13813455.2021.1890129.

  41. Martin MA, Ramos S. Impact of dietary flavanols on microbiota, immunity and inflammation in metabolic diseases. Nutrients. 2021;13:850.

  42. Martins TF, Palomino OM, Alvarez-Cilleros D, Martin MA, Ramos S, Goya L. Cocoa flavanols protect human endothelial cells from oxidative stress. Plant Foods Hum Nutr. 2020;75:161–8.

    Article  CAS  PubMed  Google Scholar 

  43. Yan T, He B, Xu M, Wu B, Xiao F, Bi K, et al. Kaempferide prevents cognitive decline via attenuation of oxidative stress and enhancement of brain-derived neurotrophic factor/tropomyosin receptor kinase B/cAMP response element-binding signaling pathway. Phytother Res. 2019;33:1065–73.

    Article  CAS  PubMed  Google Scholar 

  44. Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective. Cell. 2019;176:11–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Peng X, Wang Y, Li H, Fan J, Shen J, Yu X, et al. ATG5-mediated autophagy suppresses NF-kappaB signaling to limit epithelial inflammatory response to kidney injury. Cell Death Dis. 2019;10:253.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Li H, Peng X, Wang Y, Cao S, Xiong L, Fan J, et al. Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis. Autophagy. 2016;12:1472–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015;22:377–88.

    Article  CAS  PubMed  Google Scholar 

  48. Yun HR, Jo YH, Kim J, Shin Y, Kim SS, Choi TG. Roles of autophagy in oxidative stress. Int J Mol Sci. 2020;21:3289.

  49. Tang H, Zeng Q, Ren N, Wei Y, He Q, Chen M, et al. Kaempferide improves oxidative stress and inflammation by inhibiting the TLR4/IkappaBalpha/NF-kappaB pathway in obese mice. Iran J Basic Med Sci. 2021;24:493–8.

    PubMed  PubMed Central  Google Scholar 

  50. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO. Antioxidants accelerate lung cancer progression in mice. Sci Transl Med. 2014;6:221ra15.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82003852), the Zhejiang Provincial Natural Science Foundation (No. LYY21H310010), Zhejiang Traditional Chinese Medicine Science and Technology Project (2022ZQ010), the Fundamental Research Funds for the Central Universities (No. 2022ZFJH003), and the Adjunct Talent Fund of Zhejiang Provincial People’s Hospital.

Author information

Authors and Affiliations

  1. Center for Drug Safety Evaluation and Research; Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Yan-fei Shao, Bing-bing Tang, Yu-hui Ding, Chun-yan Fang, Ling Hong, Chun-xiao Shao, Zhao-xu Yang, Yue-ping Qiu, Jin-cheng Wang, Bo Yang, Qin-jie Weng, Jia-jia Wang & Qiao-jun He

  2. Department of Pharmacy, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, China

    Yan-fei Shao & Ling Hong

Authors
  1. Yan-fei Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bing-bing Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-hui Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun-yan Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ling Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chun-xiao Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhao-xu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yue-ping Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jin-cheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Qin-jie Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jia-jia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Qiao-jun He
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

QJH, JJW and YFS designed and interpreted experiments. YFS, BBT, YHD, CYF, LH performed experiments. CXS, ZXY, YPQ, JCW contributed to the data acquisition. QJH, JJW, YFS and TBB analyzed data and prepared the paper. BY and QJW critically reviewed the paper.

Corresponding authors

Correspondence to Jia-jia Wang or Qiao-jun He.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shao, Yf., Tang, Bb., Ding, Yh. et al. Kaempferide ameliorates cisplatin-induced nephrotoxicity via inhibiting oxidative stress and inducing autophagy. Acta Pharmacol Sin 44, 1442–1454 (2023). https://doi.org/10.1038/s41401-023-01051-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-023-01051-4

Keywords

Search

Advanced search

Quick links