Download PDF
Planta Med
DOI: 10.1055/a-2517-9234
Original Papers

Eleutherococcus senticosus Alleviates Aristolochic-Acid-Induced Acute Kidney Damage by Inhibiting the NLRP3/IL-1β Signaling Pathway in Mice

Jian-hui Zhang‡
1   Department of Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
,
Mei-zhu Gao‡
1   Department of Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
,
Qian Chen‡
1   Department of Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
,
Ting Chen‡
2   School of Medicine, Shanghai University, Shanghai, China
,
Dan-dan Ruan
1   Department of Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
,
Min Wu
1   Department of Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
,
Fang-meng Huang
1   Department of Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
,
Jie-wei Luo 
1   Department of Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
,
Yao-bin Zhu
3   Department of Traditional Chinese Medicine, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
,
Li Chen
1   Department of Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
› Author AffiliationsThis work was supported by Fujian province health science and technology plan project (2021QNB001), the Fujian Province Natural Science Fund Project (2022J01417, 2021J02 053, 2020J011 064, 2022J01 996, 2023J011 159, and 2023J011 846), the Startup Fund for scientific research of the Fujian Medical University (2021QH1272), national famous and old Chinese medicine experts (Xuemei Zhang, Yi Chunjin and Xiaohua Yan) inheritance studio construction project, the Fujian Province Medical Innovation Foundation (2022CXA001),and the Fujian Provincial Senior Talent Training Program on Western Medicine Doctors Learning from Traditional Chinese Medicine. In addition, we are grateful to Zhi-hai Zheng and Li-jun Xie, who contributed to the manuscriptʼs revision and provided partial funding for this work.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Eleutherococcus senticosus (ES) exerts various pharmacological effects, including renoprotection in a rat model of renal ischemia-reperfusion injury. However, the mechanisms of these effects remain unclear. Therefore, we investigated the effects and mechanisms of ES on aristolochic acid (AA)-induced acute kidney injury in mice. The experimental mice were divided into the control group, the model group (AA-induced acute kidney injury model), the model + ES group (Eleutherococcus senticosus boiled-free granules treated by gavage for two weeks), the model + fasudil group (fasudil administered intraperitoneally for three days), and the model + ES + fasudil group. After AA intervention in normal mice, the expression of ASC and NLRP3 and the levels of IL-1β, IL-18, and TNF-α were significantly elevated in mouse renal tissues (P < 0.05). However, AA-induced renal dysfunction was ameliorated by both ES and fasudil, which was confirmed by the decrease in serum creatinine and blood urea nitrogen levels, as well as by renal histopathological abnormalities such as renal tubule dilation and tubular formation. In addition, the inflammatory response of AA-induced renal inflammation was inhibited by both ES and fasudil, and the expression of ASC and NLRP3 and the levels of IL-1β, IL-18, and TNF-α were significantly higher in mouse renal tissues after the treatment of either ES or fasudil (P < 0.05). ES may be a potential treatment agent for aristolochic-acid-triggered nephropathy, with inhibition of the NLRP3/IL-1β as one plausible underlying mechanism.

Keywords

acute kidney damage - Araliaceae - Eleutherococcus senticosus - fasudil - aristolochic acid nephropathy - inflammatory vesicles

Supporting Information



Publication History

Received: 29 September 2024

Accepted after revision: 10 January 2025

Article published online:
24 January 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • References

  • 1 Jadot I, Decleves AE, Nortier J, Caron N. An integrated view of aristolochic acid nephropathy: Update of the literature. Int J Mol Sci 2017; 18: 297
    CrossrefPubMedSearch in Google Scholar
  • 2 Ji H, Hu J, Zhang G, Song J, Zhou X, Guo D. Aristolochic acid nephropathy: A scientometric analysis of literature published from 1971 to 2019. Medicine (Baltimore) 2021; 100: e26510
    CrossrefPubMedSearch in Google Scholar
  • 3 Katsoulieris E, Mabley JG, Samai M, Sharpe MA, Green IC, Chatterjee PK. Lipotoxicity in renal proximal tubular cells: Relationship between endoplasmic reticulum stress and oxidative stress pathways. Free Radic Biol Med 2010; 48: 1654-1662
    CrossrefPubMedSearch in Google Scholar
  • 4 Decleves AE, Jadot I, Colombaro V, Martin B, Voisin V, Nortier J, Caron N. Protective effect of nitric oxide in aristolochic acid-induced toxic acute kidney injury: An old friend with new assets. Exp Physiol 2016; 101: 193-206
    CrossrefPubMedSearch in Google Scholar
  • 5 Zhang Q, Luo P, Chen J, Yang C, Xia F, Zhang J, Tang H, Liu D, Gu L, Shi Q, He X, Yang T, Wang J. Dissection of targeting molecular mechanisms of aristolochic acid-induced nephrotoxicity via a combined deconvolution strategy of chemoproteomics and metabolomics. Int J Biol Sci 2022; 18: 2003-2017
    CrossrefPubMedSearch in Google Scholar
  • 6 Pozdzik AA, Salmon IJ, Husson CP, Decaestecker C, Rogier E, Bourgeade MF, Deschodt-Lanckman MM, Vanherweghem JL, Nortier JL. Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy. Nephrol Dial Transplant 2008; 23: 2480-2491
    CrossrefPubMedSearch in Google Scholar
  • 7 Yang L, Li X, Wang H. Possible mechanisms explaining the tendency towards interstitial fibrosis in aristolochic acid-induced acute tubular necrosis. Nephrol Dial Transplant 2007; 22: 445-456
    CrossrefPubMedSearch in Google Scholar
  • 8 Chang SY, Weber EJ, Sidorenko VS, Chapron A, Yeung CK, Gao C, Mao Q, Shen D, Wang J, Rosenquist TA, Dickman KG, Neumann T, Grollman AP, Kelly EJ, Himmelfarb J, Eaton DL. Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity. JCI Insight 2017; 2: e95978
    CrossrefPubMedSearch in Google Scholar
  • 9 Yu M, Man YL, Chen MH, Wu LH, Zhou Y, Zhou XL, Chen N, Ma R, Sun LN. Hirsutella sinensis inhibits NLRP3 inflammasome activation to block aristolochic acid-induced renal tubular epithelial cell transdifferentiation. Hum Cell 2020; 33: 79-87
    CrossrefPubMedSearch in Google Scholar
  • 10 Wen Y, Liu YR, Tang TT, Pan MM, Xu SC, Ma KL, Lv LL, Liu H, Liu BC. mROS-TXNIP axis activates NLRP3 inflammasome to mediate renal injury during ischemic AKI. Int J Biochem Cell Biol 2018; 98: 43-53
    CrossrefPubMedSearch in Google Scholar
  • 11 Wang J, Wen Y, Lv LL, Liu H, Tang RN, Ma KL, Liu BC. Involvement of endoplasmic reticulum stress in angiotensin II-induced NLRP3 inflammasome activation in human renal proximal tubular cells in vitro. Acta Pharmacol Sin 2015; 36: 821-830
    CrossrefPubMedSearch in Google Scholar
  • 12 Zhang X, Guan L, Zhu L, Wang K, Gao Y, Li J, Yan S, Ji N, Zhou Y, Yao X, Li B. A review of the extraction and purification methods, biological activities, and applications of active compounds in Acanthopanax senticosus. Front Nutr 2024; 11: 1391601
    CrossrefPubMedSearch in Google Scholar
  • 13 Jiang Y, Wang MH. Different solvent fractions of Acanthopanax senticosus harms exert antioxidant and anti-inflammatory activities and inhibit the human Kv1.3 channel. J Med Food 2015; 18: 468-475
    CrossrefPubMedSearch in Google Scholar
  • 14 Su J, Zhang X, Kan Q, Chu X. Antioxidant activity of Acanthopanax senticosus flavonoids in H(2)O(2)-induced RAW 264.7 Cells and DSS-induced colitis in mice. Molecules 2022; 27: 2872
    CrossrefPubMedSearch in Google Scholar
  • 15 Qiang L, Shubin J, Jing C, Jie W, Shaojun H, Ruigang Z. Effect of Aeanthopanax senticosus on antioxidants and serum TNF-α during acute renal ischemia-reperfusion injury in rats. Hainan Med J 2015; 7: 941-943
    CrossrefPubMedSearch in Google Scholar
  • 16 Qiang L, Shubin J, Zaixia S, Zhiyong Z, Yue C, Feng L, Shaojun H. Effect of Acanthopanax senticosus pretreatment on acute renal ischemic reperfusion injury in rats. Chinese Journal of Cell Biology 2016; 38: 1505-1511
    CrossrefPubMedSearch in Google Scholar
  • 17 Baudoux T, Jadot I, Decleves AE, Antoine MH, Colet JM, Botton O, De Prez E, Pozdzik A, Husson C, Caron N, Nortier JL. Experimental aristolochic acid nephropathy: A relevant model to study AKI-to-CKD transition. Front Med (Lausanne) 2022; 9: 822870
    CrossrefPubMedSearch in Google Scholar
  • 18 Urate S, Wakui H, Azushima K, Yamaji T, Suzuki T, Abe E, Tanaka S, Taguchi S, Tsukamoto S, Kinguchi S, Uneda K, Kanaoka T, Atobe Y, Funakoshi K, Yamashita A, Tamura K. Aristolochic acid induces renal fibrosis and senescence in mice. Int J Mol Sci 2021; 22: 12432
    CrossrefPubMedSearch in Google Scholar
  • 19 Chen D, Tang Z, Luo C, Chen H, Liu Z. Clinical and pathological spectrums of aristolochic acid nephropathy. Clin Nephrol 2012; 78: 54-60
    CrossrefPubMedSearch in Google Scholar
  • 20 Wang Y, Cui Z, Fan M. Hospital-acquired and community-acquired acute renal failure in hospitalized Chinese: A ten-year review. Ren Fail 2007; 29: 163-168
    CrossrefPubMedSearch in Google Scholar
  • 21 Zhang HM, Zhao XH, Sun ZH, Li GC, Liu GC, Sun LR, Hou JQ, Zhou W. Recognition of the toxicity of aristolochic acid. J Clin Pharm Ther 2019; 44: 157-162
    CrossrefPubMedSearch in Google Scholar
  • 22 Gokmen MR, Lord GM. Aristolochic acid nephropathy. BMJ 2012; 344: e4000
    CrossrefPubMedSearch in Google Scholar
  • 23 Grollman AP. Aristolochic acid nephropathy: Harbinger of a global iatrogenic disease. Environ Mol Mutagen 2013; 54: 1-7
    CrossrefPubMedSearch in Google Scholar
  • 24 de Zoete MR, Palm NW, Zhu S, Flavell RA. Inflammasomes. Cold Spring Harb Perspect Biol 2014; 6: a016287
    CrossrefPubMedSearch in Google Scholar
  • 25 Broderick L, De Nardo D, Franklin BS, Hoffman HM, Latz E. The inflammasomes and autoinflammatory syndromes. Annu Rev Pathol 2015; 10: 395-424
    CrossrefPubMedSearch in Google Scholar
  • 26 Huang Y, Xu W, Zhou R. NLRP3 inflammasome activation and cell death. Cell Mol Immunol 2021; 18: 2114-2127
    CrossrefPubMedSearch in Google Scholar
  • 27 Wu M, Han W, Song S, Du Y, Liu C, Chen N, Wu H, Shi Y, Duan H. NLRP3 deficiency ameliorates renal inflammation and fibrosis in diabetic mice. Mol Cell Endocrinol 2018; 478: 115-125
    CrossrefPubMedSearch in Google Scholar
  • 28 Wang S, Chen Y, Han S, Liu Y, Gao J, Huang Y, Sun W, Wang J, Wang C, Zhao J. Selenium nanoparticles alleviate ischemia reperfusion injury-induced acute kidney injury by modulating GPx-1/NLRP3/Caspase-1 pathway. Theranostics 2022; 12: 3882-3895
    CrossrefPubMedSearch in Google Scholar
  • 29 Ding W, Guo H, Xu C, Wang B, Zhang M, Ding F. Mitochondrial reactive oxygen species-mediated NLRP3 inflammasome activation contributes to aldosterone-induced renal tubular cells injury. Oncotarget 2016; 7: 17479-17491
    CrossrefPubMedSearch in Google Scholar
  • 30 Kim JY, Leem J, Jeon EJ. Protective effects of melatonin against aristolochic acid-induced nephropathy in mice. Biomolecules 2019; 10: 11
    CrossrefPubMedSearch in Google Scholar
  • 31 Li X, Tang S, Luo J, Zhang X, Yook C, Huang H, Liu X. Botany, traditional usages, phytochemistry, pharmaceutical analysis, and pharmacology of Eleutherococcus nodiflorus (Dunn) S.Y.Hu: A systematic review. J Ethnopharmacol 2023; 306: 116152
    CrossrefPubMedSearch in Google Scholar
  • 32 Jia A, Zhang Y, Gao H, Zhang Z, Zhang Y, Wang Z, Zhang J, Deng B, Qiu Z, Fu C. A review of Acanthopanax senticosus (Rupr and Maxim.) harms: From ethnopharmacological use to modern application. J Ethnopharmacol 2021; 268: 113586
    CrossrefPubMedSearch in Google Scholar
  • 33 Ni HX, Luo SS, Shao GM. [Effect of Acanthopanax senticosus injection on plasma and urinary endothelin in early stage of diabetic nephropathy]. Zhongguo Zhong Xi Yi Jie He Za Zhi 2001; 21: 105-107
    PubMedSearch in Google Scholar
  • 34 Qiang L, Shubin J, Shaojun H. Effect of Ciwujia Injection reduces renal ischemia-reperfusion injury in rats by regulating Nrf2/HO-1 pathway. Drugs & Clinic 2022; 37: 681-686
    CrossrefPubMedSearch in Google Scholar
  • 35 Ida-Naitoh M, Tokuyama H, Futatsugi K, Yasuda M, Adachi K, Kanda T, Tanabe Y, Wakino S, Itoh H. Proximal-tubule molecular relay from early Protein diaphanous homolog 1 to late Rho-associated protein kinase 1 regulates kidney function in obesity-induced kidney damage. Kidney Int 2022; 102: 798-814
    CrossrefPubMedSearch in Google Scholar
  • 36 Deng B, Yang X, Zhu Z, Zhang C. A Rho-kinase inhibitor, fasudil, attenuates progressive glomerulosclerosis induced by daunorubicin in rats. J Huazhong Univ Sci Technolog Med Sci 2009; 29: 720-724
    CrossrefPubMedSearch in Google Scholar
  • 37 Wang S, Fan J, Mei X, Luan J, Li Y, Zhang X, Chen W, Wang Y, Meng G, Ju D. Interleukin-22 Attenuated renal tubular injury in aristolochic acid nephropathy via suppressing activation of NLRP3 inflammasome. Front Immunol 2019; 10: 2277
    CrossrefPubMedSearch in Google Scholar
  • 38 Wang B, Wang Y, Tan Y, Guo J, Chen H, Wu PY, Wang X, Zhang H. Assessment of fasudil on contrast-associated acute kidney injury using multiparametric renal MRI. Front Pharmacol 2022; 13: 905547
    CrossrefPubMedSearch in Google Scholar
  • 39 Chao-Ying Y, Yang J, Di Q, Dao-Xin W. Effect of fasudil attenuates acute lung injury induced by lipopolysaccharide and its mechanism. Medical Journal of Chinese Peopleʼs Liberation Army 2023; 48: 27-33
    CrossrefPubMedSearch in Google Scholar
  • 40 Jing T, Jianping L, Rui C. Pharmacokinetic studies of radix acanthopanacis senticosis suspension. Traditional Chinese Drug Research and Clinical Pharmacology 2003; 14: 319-320
    CrossrefPubMedSearch in Google Scholar
  • 41 Dominic A, Le NT, Takahashi M. Loop between NLRP3 inflammasome and reactive oxygen species. Antioxid Redox Signal 2022; 36: 784-796
    CrossrefPubMedSearch in Google Scholar
  • 42 Wang YL, Lee YH, Hsu YH, Chiu IJ, Huang CC, Huang CC, Chia ZC, Lee CP, Lin YF, Chiu HW. The Kidney-related effects of polystyrene microplastics on human kidney proximal tubular epithelial cells HK-2 and male C57BL/6 mice. Environ Health Perspect 2021; 129: 57003
    CrossrefPubMedSearch in Google Scholar
  • 43 Wang X, Xue N, Zhao S, Shi Y, Ding X, Fang Y. Upregulation of miR-382 contributes to renal fibrosis secondary to aristolochic acid-induced kidney injury via PTEN signaling pathway. Cell Death Dis 2020; 11: 620
    CrossrefPubMedSearch in Google Scholar
  • 44 Wang YD, Zhang L, Cai GY, Zhang XG, Lv Y, Hong Q, Shi SZ, Yin Z, Liu XF, Chen XM. Fasudil ameliorates rhabdomyolysis-induced acute kidney injury via inhibition of apoptosis. Ren Fail 2011; 33: 811-818
    CrossrefPubMedSearch in Google Scholar