Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Saponins from Panax japonicus ameliorate age-related renal fibrosis by inhibition of inflammation mediated by NF-κB and TGF-β1/Smad signaling and suppression of oxidative stress via activation of Nrf2-ARE signaling

  • Gao, Yan (College of Medical Science, China Three Gorges University) ;
  • Yuan, Ding (College of Medical Science, China Three Gorges University) ;
  • Gai, Liyue (College of Medical Science, China Three Gorges University) ;
  • Wu, Xuelian (College of Medical Science, China Three Gorges University) ;
  • Shi, Yue (College of Medical Science, China Three Gorges University) ;
  • He, Yumin (College of Medical Science, China Three Gorges University) ;
  • Liu, Chaoqi (College of Medical Science, China Three Gorges University) ;
  • Zhang, Changcheng (College of Medical Science, China Three Gorges University) ;
  • Zhou, Gang (College of Traditional Chinese Medicine, China Three Gorges University) ;
  • Yuan, Chengfu (College of Medical Science, China Three Gorges University)
  • Received : 2020.04.14
  • Accepted : 2020.08.26
  • Published : 2021.05.01
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Abstract

Background: The decreased renal function is known to be associated with biological aging, of which the main pathological features are chronic inflammation and renal interstitial fibrosis. In previous studies, we reported that total saponins from Panax japonicus (SPJs) can availably protect acute myocardial ischemia. We proposed that SPJs might have similar protective effects for aging-associated renal interstitial fibrosis. Thus, in the present study, we evaluated the overall effect of SPJs on renal fibrosis. Methods: Sprague-Dawley (SD) aging rats were given SPJs by gavage beginning from 18 months old, at 10 mg/kg/d and 60 mg/kg/d, up to 24 months old. After the experiment, changes in morphology, function and fibrosis of their kidneys were detected. The levels of serum uric acid (UA), β2-microglobulin (β2-MG) and cystatin C (Cys C) were assayed with ELISA kits. The levels of extracellular matrix (ECM), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), inflammatory factors and changes of oxidative stress parameters were examined. Results: After SPJs treatment, SD rats showed significantly histopathological changes in kidneys accompanied by decreased renal fibrosis and increased renal function; As compared with those in 3-month group, the levels of serum UA, Cys C and β2-MG in 24-month group were significantly increased (p < 0.05). Compared with those in the 24-month group, the levels of serum UA, Cys C and β2-MG in the SPJ-H group were significantly decreased. While ECM was reduced and the levels of MMP-2 and MMP-9 were increased, the levels of TIMP-1, TIMP-2 and transforming growth factor-β1 (TGF-β1)/Smad signaling were decreased; the expression level of phosphorylated nuclear factor kappa-B (NF-κB) was down-regulated with reduced inflammatory factors; meanwhile, the expression of nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) signaling was aggrandized. Conclusion: These results suggest that SPJs treatment can improve age-associated renal fibrosis by inhibiting TGF-β1/Smad, NFκB signaling pathways and activating Nrf2-ARE signaling pathways and that SPJs can be a potentially valuable anti-renal fibrosis drug.

Keywords

Acknowledgement

This study was financially supported by grants from National Natural Science Foundation of China (Grant No. 81773959 to C.F. Yuan and No. 81974528 to C.F. Yuan) and Health Commission of Hubei Province Scientific Research Project in China. (Grant No. WJ2019H527 to C.F. Yuan)

References

  1. Rule AD, Amer H, Cornell LD, Taler SJ, Cosio FG, Kremers WK, Textor SC, Stegall MD. The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann Intern Med 2010;152(9):561-7. https://doi.org/10.7326/0003-4819-152-9-201005040-00006
  2. Xie L, Cianciolo RE, Hulette B, Lee HW, Qi Y, Cofer G, Johnson GA. Magnetic resonance histology of age-related nephropathy in the Sprague Dawley rat. Toxicol Pathol 2012;40(5):764-78. https://doi.org/10.1177/0192623312441408
  3. Luyckx VA, Tonelli M, Stanifer JW. The global burden of kidney disease and the sustainable development goals. Bull World Health Organ 2018;96(6):414-422D. https://doi.org/10.2471/BLT.17.206441
  4. Portilla D. Apoptosis, fibrosis and senescence. Nephron Clin Pract 2014;127(1-4):65-9. https://doi.org/10.1159/000363717
  5. Zhou X, Zhang J, Xu C, Wang W. Curcumin ameliorates renal fibrosis by inhibiting local fibroblast proliferation and extracellular matrix deposition. J Pharmacol Sci 2014;126(4):344-50. https://doi.org/10.1254/jphs.14173FP
  6. Ni WJ, Ding HH, Zhou H, Qiu YY, Tang LQ. Renoprotective effects of berberine through regulation of the MMPs/TIMPs system in streptozocin-induced diabetic nephropathy in rats. Eur J Pharmacol 2015;764:448-56. https://doi.org/10.1016/j.ejphar.2015.07.040
  7. Lan HY. Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation. Int J Biol Sci 2011;7(7):1056-67. https://doi.org/10.7150/ijbs.7.1056
  8. Lan HY, Chung AC. TGF-beta/Smad signaling in kidney disease. Semin Nephrol 2012;32(3):236-43. https://doi.org/10.1016/j.semnephrol.2012.04.002
  9. Montecino-Rodriguez E, Berent-Maoz B, Dorshkind K. Causes, consequences, and reversal of immune system aging. J Clin Invest 2013;123(3):958-65. https://doi.org/10.1172/JCI64096
  10. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nat Rev Immunol 2013;13(12):875-87. https://doi.org/10.1038/nri3547
  11. Adler AS, Kawahara TL, Segal E, Chang HY. Reversal of aging by NFkappaB blockade. Cell Cycle 2008;7(5):556-9. https://doi.org/10.4161/cc.7.5.5490
  12. Perkins ND. Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 2007;8(1):49-62. https://doi.org/10.1038/nrm2083
  13. Hoffmann A, Natoli G, Ghosh G. Transcriptional regulation via the NF-kappaB signaling module. Oncogene 2006;25(51):6706-16. https://doi.org/10.1038/sj.onc.1209933
  14. Siems W, Quast S, Carluccio F, Wiswedel I, Hirsch D, Augustin W, Hampi H, Riehle M, Sommerburg O. Oxidative stress in chronic renal failure as a cardiovascular risk factor. Clin Nephrol 2002;58(Suppl 1):S12-9.
  15. Al-Sheikh YA, Ghneim HK, Aljaser FS, Aboul-Soud MAM. Ascorbate ameliorates Echis coloratus venom-induced oxidative stress in human fibroblasts. Exp Ther Med 2017;14(1):703-13. https://doi.org/10.3892/etm.2017.4522
  16. Yuan C, Wang C, Bu Y, Xiang T, Huang X, Wang Z, Yi F, Ren G, Liu G, Song F. Antioxidative and immunoprotective effects of Pyracantha fortuneana (Maxim.) Li polysaccharides in mice. Immunol Lett 2010;133(1):14-8. https://doi.org/10.1016/j.imlet.2010.04.004
  17. Hyun SH, Kim SW, Seo HW, Youn SH, Kyung JS, Lee YY, In G, Park CK, Han CK. Physiological and pharmacological features of the non-saponin components in Korean Red Ginseng. J Ginseng Res 2020;44(4):527-37. https://doi.org/10.1016/j.jgr.2020.01.005
  18. Song YN, Yuan D, Zhang CC, Wang LP, He YM, Wang T, Zhou ZY. Effect of saponins extracted from Panax japonicus on inhibiting cardiomyocyte apoptosis by AMPK/Sirt1/NF-kappaB signaling pathway in aging rats. Zhongguo Zhong Yao Za Zhi 2017;42(23):4656-60.
  19. Deng LL, Yuan D, Zhou ZY, Wan JZ, Zhang CC, Liu CQ, Dun YY, Zhao HX, Zhao B, Yang YJ, et al. Saponins from Panax japonicus attenuate age-related neuroinflammation via regulation of the mitogen-activated protein kinase and nuclear factor kappa B signaling pathways. Neural Regen Res 2017;12(11):1877-84. https://doi.org/10.4103/1673-5374.219047
  20. Wang T, Di G, Yang L, Dun Y, Sun Z, Wan J, Peng B, Liu C, Xiong G, Zhang C, et al. Saponins from Panax japonicus attenuate D-galactose-induced cognitive impairment through its anti-oxidative and anti-apoptotic effects in rats. J Pharm Pharmacol 2015;67(9):1284-96. https://doi.org/10.1111/jphp.12413
  21. Wei N, Zhang C, He H, Wang T, Liu Z, Liu G, Sun Z, Zhou Z, Bai C, Yuan D. Protective effect of saponins extract from Panax japonicus on myocardial infarction: involvement of NF-κB, Sirt1 and mitogen-activated protein kinase signalling pathways and inhibition of inflammation. J Pharm Pharmacol 2014;66(11):1641-51. https://doi.org/10.1111/jphp.12291
  22. He H, Xu J, Xu Y, Zhang C, Wang H, He Y, Wang T, Yuan D. Cardioprotective effects of saponins from Panax japonicus on acute myocardial ischemia against oxidative stress-triggered damage and cardiac cell death in rats. J Ethnopharmacol 2012;140(1):73-82. https://doi.org/10.1016/j.jep.2011.12.024
  23. Karam Z, Tuazon J. Anatomic and physiologic changes of the aging kidney. Clin Geriatr Med 2013;29(3):555-64. https://doi.org/10.1016/j.cger.2013.05.006
  24. Tang R, Zhou QL, Ao X, Peng WS, Veeraragoo P, Tang TF. Fosinopril and losartan regulate klotho gene and nicotinamide adenine dinucleotide phosphate oxidase expression in kidneys of spontaneously hypertensive rats. Kidney Blood Press Res 2011;34(5):350-7. https://doi.org/10.1159/000326806
  25. Pang M, Kothapally J, Mao H, Tolbert E, Ponnusamy M, Chin YE, Zhuang S. Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy. Am J Physiol Renal Physiol 2009;297(4):F996-f1005. https://doi.org/10.1152/ajprenal.00282.2009
  26. Back M, Ketelhuth DF, Agewall S. Matrix metalloproteinases in atherothrombosis. Prog Cardiovasc Dis 2010;52(5):410-28. https://doi.org/10.1016/j.pcad.2009.12.002
  27. Thrailkill KM, Clay Bunn R, Fowlkes JL. Matrix metalloproteinases: their potential role in the pathogenesis of diabetic nephropathy. Endocrine 2009;35(1):1-10. https://doi.org/10.1007/s12020-008-9114-6
  28. Racca MA, Novoa PA, Rodriguez I, Della Vedova AB, Pellizas CG, Demarchi M, Donadio AC. Renal dysfunction and intragraft proMMP9 activity in renal transplant recipients with interstitial fibrosis and tubular atrophy. Transpl Int 2015;28(1):71-8. https://doi.org/10.1111/tri.12445
  29. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003;92(8):827-39. https://doi.org/10.1161/01.RES.0000070112.80711.3D
  30. Sharma AK, Mauer SM, Kim Y, Michael AF. Altered expression of matrix metalloproteinase-2, TIMP-1, and TIMP-2 in obstructive nephropathy. J Lab Clin Med 1995;125(6):754-61.
  31. Yao Z, Yang S, He W, Li L, Xu R, Zhang X, Li H, Zhan R, Sun W, Tan J, et al. P311 promotes renal fibrosis via TGFbeta1/Smad signaling. Sci Rep 2015;5:17032. https://doi.org/10.1038/srep17032
  32. Choi ME, Ding Y, Kim SI. TGF-beta signaling via TAK1 pathway: role in kidney fibrosis. Semin Nephrol 2012;32(3):244-52. https://doi.org/10.1016/j.semnephrol.2012.04.003
  33. Wada T, Sakai N, Matsushima K, Kaneko S. Fibrocytes: a new insight into kidney fibrosis. Kidney Int 2007;72(3):269-73. https://doi.org/10.1038/sj.ki.5002325
  34. Misseri R, Meldrum DR, Dagher P, Hile K, Rink RC, Meldrum KK. Unilateral ureteral obstruction induces renal tubular cell production of tumor necrosis factor-alpha independent of inflammatory cell infiltration. J Urol 2004;172(4 Pt 2):1595-9. discussion 1599. https://doi.org/10.1097/01.ju.0000138902.57626.70
  35. Chaves de Souza JA, Nogueira AV, Chaves de Souza PP, Kim YJ, Silva Lobo C, Pimentel Lopes de Oliveira GJ, Cirelli JA, Garlet GP, Rossa Jr C. SOCS3 expression correlates with severity of inflammation, expression of proinflammatory cytokines, and activation of STAT3 and p38 MAPK in LPS-induced inflammation in vivo. Mediators Inflamm 2013;2013:650812.
  36. Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev 2012;92(2):689-737. https://doi.org/10.1152/physrev.00028.2011
  37. Qin T, Yin S, Yang J, Zhang Q, Liu Y, Huang F, Cao W. Sinomenine attenuates renal fibrosis through Nrf2-mediated inhibition of oxidative stress and TGFβ signaling. Toxicol Appl Pharmacol 2016;304:1-8. https://doi.org/10.1016/j.taap.2016.05.009
  38. Abdelkhalek NK, Ghazy EW, Abdel-Daim MM. Pharmacodynamic interaction of Spirulina platensis and deltamethrin in freshwater fish Nile tilapia, Oreochromis niloticus: impact on lipid peroxidation and oxidative stress. Environ Sci Pollut Res Int 2015;22(4):3023-31. https://doi.org/10.1007/s11356-014-3578-0
  39. Wasik U, Milkiewicz M, Kempinska-Podhorodecka A, Milkiewicz P. Protection against oxidative stress mediated by the Nrf2/Keap1 axis is impaired in Primary Biliary Cholangitis. Sci Rep 2017;7:44769. https://doi.org/10.1038/srep44769
  40. Chen Z, Xie X, Huang J, Gong W, Zhu X, Chen Q, Huang J, Huang H. Connexin43 regulates high glucose-induced expression of fibronectin, ICAM-1 and TGF-beta1 via Nrf2/ARE pathway in glomerular mesangial cells. Free Radic Biol Med 2017;102:77-86. https://doi.org/10.1016/j.freeradbiomed.2016.11.015
  41. Zhou W, Mo X, Cui W, Zhang Z, Li D, Li L, Xu L, Yao H, Gao J. Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis. Sci Rep 2016;6:38646. https://doi.org/10.1038/srep38646
  42. Lacher SE, Slattery M. Gene regulatory effects of disease-associated variation in the NRF2 network. Curr Opin Toxicol 2016;1:71-9. https://doi.org/10.1016/j.cotox.2016.09.001
  43. Kim EN, Lim JH, Kim MY, Kim HW, Park CW, Chang YS, Choi BS. PPARalpha agonist, fenofibrate, ameliorates age-related renal injury. Exp Gerontol 2016;81:42-50. https://doi.org/10.1016/j.exger.2016.04.021
  44. Qiao Y, Xu L, Tao X, Yin L, Qi Y, Xu Y, Han X, Tang Z, Ma X, Liu K, 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. https://doi.org/10.1016/j.toxlet.2017.11.031