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.
schisandrin B IgA nephropathy renal function TNF-alpha NF-κB
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This research was financially supported by the Medical Research Project of the Sichuan Medical Association (No. 201363).
Compliance and Ethical Standards
Conflicts of Interest
All contributing authors declare that they have no conflicts of interest.
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.
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedPubMedCentralGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedPubMedCentralGoogle Scholar
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.CrossRefGoogle Scholar
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.
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedPubMedCentralGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefGoogle Scholar
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.PubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.PubMedPubMedCentralGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.PubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.CrossRefPubMedGoogle Scholar
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.Google Scholar
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.CrossRefPubMedGoogle Scholar
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.PubMedGoogle Scholar