Schisandrin B Improves the Renal Function of IgA Nephropathy Rats Through Inhibition of the NF-κB Signalling Pathway

Abstract

Schisandrin B (SchB) is an active compound extracted from the Chinese herb Schisandra chinensis and shows excellent anti-inflammatory activity. This study was performed to examine the effects of SchB in a rat model of IgA nephropathy (IgAN). IgAN was established in Sprague-Dawley rats by immunization with lipopolysaccharide (LPS), bovine serum albumin, and carbon tetrachloride. Renal function was evaluated by determining the levels of urinary red blood cells, proteinuria, blood urea nitrogen (BUN), and creatinine (Cr). Renal tissue and protein samples were collected for further analysis. Pre-treatment and treatment with SchB significantly ameliorated renal function of IgAN rats, which was evidenced by decreased levels of proteinuria, hematuria, BUN, and Cr. IgAN rats exhibited increased serum IgA, renal IgA deposition, mesangial cell proliferation, and inflammatory cell infiltration, which were significantly attenuated by intervention with SchB. Moreover, SchB inhibited infiltration of CD3+ and CD11b+ cells, decreased levels of tumour necrosis factor-alpha, interleukin-1β, and monocyte chemoattractant protein-1 in the kidney, and decreased the numbers of CD3+CD69+ cells in the spleen. Of note, SchB therapy significantly increased cytoplasmic p65 and IκB expression and decreased nuclear p65 levels both in the damaged renal tissue and LPS-stimulated HK-2 cells, indicating a direct inhibitory effect on the NF-κB pathway in IgAN rats. Taken together, our data provide insight into a new application of SchB for the treatment of IgAN and represent a novel mechanism behind these effects.

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References

  1. 1.

    Lai, K.N., S.C. Tang, F.P. Schena, J. Novak, Y. Tomino, A.B. Fogo, and R.J. Glassock. 2016. IgA nephropathy. Nature Reviews Disease Primers 2: 16001.

    Article  Google Scholar 

  2. 2.

    Xie, Y., and X. Chen. 2008. Epidemiology, major outcomes, risk factors, prevention and management of chronic kidney disease in China. American Journal of Nephrology 28: 1–7.

    Article  Google Scholar 

  3. 3.

    Katafuchi, R., K. Ikeda, T. Mizumasa, H. Tanaka, T. Ando, T. Yanase, K. Masutani, M. Kubo, and S. Fujimi. 2003. Controlled, prospective trial of steroid treatment in IgA nephropathy: A limitation of low-dose prednisolone therapy. American Journal of Kidney Diseases 41: 972–983.

    CAS  Article  Google Scholar 

  4. 4.

    Pozzi, C., P.G. Bolasco, G.B. Fogazzi, S. Andrulli, P. Altieri, C. Ponticelli, and F. Locatelli. 1999. Corticosteroids in IgA nephropathy: A randomised controlled trial. Lancet 353: 883–887.

    CAS  Article  Google Scholar 

  5. 5.

    Lan, H.Y., D.J. Paterson-Nikolic, W. Mu, and R.C. Atkins. 1997. Local macrophage proliferation in the pathogenesis of glomerular crescent formation in rat anti-glomerular basement membrane (GBM) glomerulonephritis. Clinical and Experimental Immunology 110: 233–240.

    CAS  Article  Google Scholar 

  6. 6.

    Ka, S.M., T.T. Hsieh, S.H. Lin, S.S. Yang, C.C. Wu, H.K. Sytwu, and A. Chen. 2011. Decoy receptor 3 inhibits renal mononuclear leukocyte infiltration and apoptosis and prevents progression of IgA nephropathy in mice. American Journal of Physiology-Renal Physiology 301: F1218–F1230.

    CAS  Article  Google Scholar 

  7. 7.

    Stangou, M., C. Bantis, M. Skoularopoulou, L. Korelidou, D. Kouloukouriotou, M. Scina, I.T. Labropoulou, N.M. Kouri, A. Papagianni, and G. Efstratiadis. 2016. Th1, Th2 and Treg/T17 cytokines in two types of proliferative glomerulonephritis. Indian Journal of Nephrology 26: 159–166.

    CAS  Article  Google Scholar 

  8. 8.

    Chen, Q., H. Zhang, Y. Cao, Y. Li, S. Sun, J. Zhang, and G. Zhang. 2017. Schisandrin B attenuates CCl4-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-β/Smad signaling pathways. Drug Design Development and Therapy 11: 2179–2191.

    CAS  Article  Google Scholar 

  9. 9.

    Sun, R., R. Zhai, C. Ma, and M. Wei. 2017, 2017. The anti-growth and anti-metastasis effects of Schisandrin B on hepatocarcinoma cells in vitro and in vivo. Biochemical and Biophysical Research Communications. https://doi.org/10.1016/j.bbrc.2017.06.022.

  10. 10.

    Lin, Q., X. Qin, M. Shi, Z. Qin, Y. Meng, Z. Qin, and S. Guo. 2017. Schisandrin B inhibits LPS-induced inflammatory response in human umbilical vein endothelial cells by activating Nrf2. International Immunopharmacology 49: 142–147.

    CAS  Article  Google Scholar 

  11. 11.

    Zhang, W., Z. Sun, and F. Meng. 2017. Schisandrin B ameliorates myocardial ischemia/reperfusion injury through attenuation of endoplasmic reticulum stress-induced apoptosis. Inflammation 40: 1903–1911.

    CAS  Article  Google Scholar 

  12. 12.

    Xu, Y., Z. Liu, J. Sun, Q. Pan, F. Sun, Z. Yan, and X. Hu. 2011. Schisandrin B prevents doxorubicin- induced chronic cardiotoxicity and enhances its anticancer activity in vivo. PLoS One 6: e28335.

    CAS  Article  Google Scholar 

  13. 13.

    Ko, K.M., and B.Y. Lam. 2002. Schisandrin B protects against tert-butylhydroperoxide induced cerebral toxicity by enhancing glutathione antioxidant status in mouse brain. Molecular and Cellular Biochemistry 238: 181–186.

    CAS  Article  Google Scholar 

  14. 14.

    Chen, Z., M. Guo, G. Song, J. Gao, Y. Zhang, Z. Jing, T. Liu, and C. Dong. 2016. Schisandrin B inhibits Th1/Th17 differentiation and promotes regulatory T cell expansion in mouse lymphocytes. International Immunopharmacology 35: 257–264.

    CAS  Article  Google Scholar 

  15. 15.

    Leong, P.K., and K.M. Ko. 2015. Schisandrin B induces an Nrf2-mediated thioredoxin expression and suppresses the activation of inflammasome in vitro and in vivo. Biofactors 41: 314–323.

    CAS  Article  Google Scholar 

  16. 16.

    Checker, R., R.S. Patwardhan, D. Sharma, J. Menon, M. Thoh, H.N. Bhilwade, T. Konishi, and S.K. Sandur. 2012. Schisandrin B exhibits anti-inflammatory activity through modulation of the redox-sensitive transcription factors Nrf2 and NF-κB. Free Radical Biology and Medicine 53: 1421–1430.

    CAS  Article  Google Scholar 

  17. 17.

    Park, E.J., J.N. Chun, S.H. Kim, C.Y. Kim, H.J. Lee, H.K. Kim, J.K. Park, S.W. Lee, I. So, and J.H. Jeon. 2012. Schisandrin B suppresses TGFβ1 signaling by inhibiting Smad2/3 and MAPK pathways. Biochemical Pharmacology 83: 378–384.

    CAS  Article  Google Scholar 

  18. 18.

    Chiu, P.Y., H.Y. Leung, and K.M. Ko. 2008. Schisandrin B enhances renal mitochondrial antioxidant status, functional and structural integrity, and protects against gentamicin-induced nephrotoxicity in rats. Biological & Pharmaceutical Bulletin 31: 602–605.

    CAS  Article  Google Scholar 

  19. 19.

    Zhu, S., Y. Wang, M. Chen, J. Jin, Y. Qiu, M. Huang, and Z. Huang. 2012. Protective effect of schisandrin B against cyclosporine A-induced nephrotoxicity in vitro and in vivo. American Journal of Chinese Medicine 40: 551–566.

    CAS  Article  Google Scholar 

  20. 20.

    Stacchiotti, A., Volti.G. Li, A. Lavazza, I. Schena, M.F. Aleo, L.F. Rodella, and R. Rezzani. 2011. Different role of Schisandrin B on mercury-induced renal damage in vivo and in vitro. Toxicology 286: 48–57.

    CAS  Article  Google Scholar 

  21. 21.

    Wei, L., Y. Du, L. Jia, X. Ma, Z. Chen, J. Lu, L. Tian, Z. Duan, F. Dong, Z. Lv, G. Yao, R. Fu, and L. Wang. 2017. Therapeutic effects of FK506 on IgA nephropathy rat. Kidney & Blood Pressure Research 42: 983–998.

    CAS  Article  Google Scholar 

  22. 22.

    Lai, K.N., L.Y. Chan, H. Guo, S.C. Tang, and J.C. Leung. 2011. Additive effect of PPAR-γ agonist and ARB in treatment of experimental IgA nephropathy. Pediatric Nephrology 26: 257–266.

    Article  Google Scholar 

  23. 23.

    Hu, Y., Z. Hu, S. Wang, X. Dong, C. Xiao, M. Jiang, A. Lv, W. Zhang, and R. Liu. 2013. Protective effects of Huang-Lian-Jie-Du-Tang and its component group on collagen-induced arthritis in rats. Journal of Ethnopharmacology 150: 1137–1144.

    Article  Google Scholar 

  24. 24.

    Cox, S.N., G. Serino, F. Sallustio, A. Blasi, M. Rossini, F. Pesce, and F.P. Schena. 2015. Altered monocyte expression and expansion of non-classical monocyte subset in IgA nephropathy patients. Nephrology Dialysis Transplantation 30: 1122–1232.

    CAS  Article  Google Scholar 

  25. 25.

    Sakatsume, M., Y. Xie, M. Ueno, H. Obayashi, S. Goto, I. Narita, N. Homma, K. Tasaki, Y. Suzuki, and F. Gejyo. 2001. Human glomerulonephritis accompanied by active cellular infiltrates shows effector T cells in urine. Journal of the American Society of Nephrology 12: 2636–2644.

    CAS  PubMed  Google Scholar 

  26. 26.

    Wu, T.H., S.C. Wu, T.P. Huang, C.L. Yu, and C.Y. Tsai. 1996. Increased excretion of tumor necrosis factor alpha and interleukin 1 beta in urine from patients with IgA nephropathy and Schönlein-Henoch purpura. Nephron 74: 79–88.

    CAS  Article  Google Scholar 

  27. 27.

    Lim, C.S., S. Zheng, Y.S. Kim, C. Ahn, J.S. Han, S. Kim, J.S. Lee, D.W. Chae, J.R. Koo, R.W. Chun, and J.W. Noh. 2001. Th1/Th2 predominance and proinflammatory cytokines determine the clinicopathological severity of IgA nephropathy. Nephrology Dialysis Transplantation 16: 269–275.

    CAS  Article  Google Scholar 

  28. 28.

    Syrjänen, J., M. Hurme, T. Lehtimäki, J. Mustonen, and A. Pasternack. 2002. Polymorphism of the cytokine genes and IgA nephropathy. Kidney International 61: 1079–1085.

    Article  Google Scholar 

  29. 29.

    Lee, S.H., E.J. Lee, S.W. Chung, R. Song, J.Y. Moon, S.H. Lee, S.J. Lim, Y.A. Lee, S.J. Hong, and H.I. Yang. 2013. Renal involvement in ankylosing spondylitis: Prevalence, pathology, response to TNF-a blocker. Rheumatology International 33: 1689–1692.

    CAS  Article  Google Scholar 

  30. 30.

    Lai, K.N., J.C. Leung, L.Y. Chan, M.A. Saleem, P.W. Mathieson, F.M. Lai, and S.C. Tang. 2008. Activation of podocytes by mesangial-derived TNF-alpha: Glomerulo-podocytic communication in IgA nephropathy. American Journal of Physiology-Renal Physiology 294: F945–F955.

    CAS  Article  Google Scholar 

  31. 31.

    Guo, Y., Z. Song, M. Zhou, Y. Yang, Y. Zhao, B. Liu, and X. Zhang. 2017. Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway. Oncotarget 8: 53276–53287.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Nee, L., N. Tuite, M.P. Ryan, and T. McMorrow. 2007. TNF-alpha and IL-1 beta-mediated regulation of MMP-9 and TIMP-1 in human glomerular mesangial cells. Nephron Experimental Nephrology 107: e73–e86.

    CAS  Article  Google Scholar 

  33. 33.

    Tesch, G.H., H.Y. Lan, R.C. Atkins, and D.J. Nikolic-Paterson. 1997. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. American Journal of Pathology 151: 141–150.

    CAS  PubMed  Google Scholar 

  34. 34.

    Zeng, K.W., T. Zhang, H. Fu, G.X. Liu, and X.M. Wang. 2012. Schisandrin B exerts anti-neuroinflammatory activity by inhibiting the Toll-like receptor 4-dependent MyD88/IKK/NF-κB signaling pathway in lipopolysaccharide-induced microglia. European Journal of Pharmacology 692: 29–37.

    CAS  Article  Google Scholar 

  35. 35.

    Cai, Z., J. Liu, H. Bian, J. Cai, and G. Zhu. 2016. Suppression of P2X7/NF-κB pathways by Schisandrin B contributes to attenuation of lipopolysaccharide-induced inflammatory responses in acute lung injury. Archives of Pharmacal Research 39: 499–507.

    CAS  Article  Google Scholar 

  36. 36.

    Kopitar-Jerala, N. 2015. Innate immune response in brain, NF-kappa B signaling and cystatins. Frontiers in Molecular Neuroscience 8: 73.

    Article  Google Scholar 

  37. 37.

    Park, M.H., and J.T. Hong. 2016. Roles of NF-κB in cancer and inflammatory diseases and their therapeutic approaches. Cells 5(2). pii: E15.

  38. 38.

    Giridharan, V.V., R.A. Thandavarayan, H.N. Bhilwade, K.M. Ko, K. Watanabe, and T. Konishi. 2012. Schisandrin B, attenuates cisplatin-induced oxidative stress, genotoxicity and neurotoxicity through modulating NF-κB pathway in mice. Free Radical Research 46: 50–60.

    Article  Google Scholar 

  39. 39.

    Liu, W., Y. Liu, Z. Wang, T. Yu, Q. Lu, and H. Chen. 2015. Suppression of MAPK and NF-κ B pathways by schisandrin B contributes to attenuation of DSS-induced mice model of inflammatory bowel disease. Pharmazie 70: 598–603.

    PubMed  Google Scholar 

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Acknowledgements

This research was financially supported by the Medical Research Project of the Sichuan Medical Association (No. 201363).

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Correspondence to Wei-Hua Wu.

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The present study was approved by the Animal Care and Use Committee of Southwest Medical University (Luzhou, China), and all procedures performed in the studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Qin, J., Lin, J., Ding, W. et al. Schisandrin B Improves the Renal Function of IgA Nephropathy Rats Through Inhibition of the NF-κB Signalling Pathway. Inflammation 42, 884–894 (2019). https://doi.org/10.1007/s10753-018-0943-z

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KEY WORDS

  • schisandrin B
  • IgA nephropathy
  • renal function
  • TNF-alpha
  • NF-κB