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Silibinin enhances anti-renal fibrosis effect of MK-521 via downregulation of TGF-β signaling pathway

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Abstract

Renal fibrosis is a common characteristic of chronic kidney disease (CKD), and it can lead to end-stage renal disease. It has been reported that silibinin or lisinopril (MK-521) can inhibit the progression of renal fibrosis. However, the effect of combination of silibinin with MK-521 on renal fibrosis remains unclear. Therefore, this study aimed to explore the combination of silibinin with MK-521 on renal fibrosis in vitro and in vivo. The cell viability of HK-2 was detected by CCK-8. The gene and protein expression in HK-2 cells were detected by qRT-PCR and Western blot, respectively. Moreover, HFD-induced renal fibrosis mouse model was established to investigate the effect of silibinin in combination with MK-521 on renal fibrosis in vivo. The expressions of collagen I, α-SMA, Smad2 and Smad3 in TGF-β-treated HK-2 cells were notably decreased by MK-521, which was further inhibited in the presence of silibinin. In addition, we found that silibinin significantly enhanced anti-fibrotic effect of MK-521 on HFD-induced renal fibrosis mice. These findings demonstrated that silibinin could significantly increase anti-fibrotic effect of MK-521 in vitro and in vivo. Therefore, the combination of silibinin with MK-521 may serve as a potential strategy for the treatment of renal fibrosis.

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References

  1. Hewitson TD. Renal tubulointerstitial fibrosis: common but never simple. Am J Physiol Renal Physiol. 2009;296:F1239–44.

    Article  CAS  Google Scholar 

  2. Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 2011;7:684–96.

    Article  CAS  Google Scholar 

  3. Santos-Paul MA, Neves RS, Gowdak LHW, et al. Cardiovascular risk reduction with periodontal treatment in patients on the waiting list for renal transplantation. Clin Transplant. 2019;4:e13658.

    Google Scholar 

  4. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382:260–72.

    Article  Google Scholar 

  5. Diwan V, Brown L, Gobe GC. Adenine-induced chronic kidney disease in rats. Nephrology (Carlton). 2018;23:5–11.

    Article  CAS  Google Scholar 

  6. Jacobs ER, Narayanan J, Fish BL, et al. Cardiac remodeling and reversible pulmonary hypertension during pneumonitis in rats after 13-Gy partial-body irradiation with minimal bone marrow sparing: effect of lisinopril. Health Phys. 2019;116:558–65.

    Article  CAS  Google Scholar 

  7. Cuevas CA, Tapia-Rojas C, Cespedes C, Inestrosa NC, Vio CP. Beta-catenin-dependent signaling pathway contributes to renal fibrosis in hypertensive rats. Biomed Res Int. 2015;2015:726012.

    Article  Google Scholar 

  8. Asgharzadeh F, Hashemzehi M, Marjaneh RM, et al. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as therapeuticoptions in the treatment of renal cancer: a meta-analysis. Life Sci. https://doi.org/10.1016/j.lfs.2019.117181

    Article  Google Scholar 

  9. Bhatia N, Zhao J, Wolf DM, Agarwal R. Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett. 1999;147:77–84.

    Article  CAS  Google Scholar 

  10. Liu Y, Ye J, Cao Y, et al. Silibinin ameliorates diabetic nephropathy via improving diabetic condition in the mice. Eur J Pharmacol. 2019;845:24–31.

    Article  CAS  Google Scholar 

  11. Li F, Ma Z, Guan Z, et al. Autophagy induction by silibinin positively contributes to its anti-metastatic capacity via AMPK/mTOR pathway in renal cell carcinoma. Int J Mol Sci. 2015;16:8415–29.

    Article  CAS  Google Scholar 

  12. Liu K, Zhou S, Liu J, Wang Y, Zhu F, Liu M. Silibinin attenuates high-fat diet-induced renal fibrosis of diabetic nephropathy. Drug Des Dev Ther. 2019;13:3117–26.

    Article  Google Scholar 

  13. Balys M, Dabek J, Glogowska-Ligus J, Gasior Z. Transcriptional activity of transforming growth factor beta 1 gene and its receptors in patients with early stages of coronary artery disease. Miner Med. 2019;110:92–4.

    Google Scholar 

  14. Meng XM, Zhang Y, Huang XR, Ren GL, Li J, Lan HY. Treatment of renal fibrosis by rebalancing TGF-beta/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget. 2015;6:36984–97.

    PubMed  PubMed Central  Google Scholar 

  15. Munoz-Felix JM, Gonzalez-Nunez M, Martinez-Salgado C, Lopez-Novoa JM. TGF-beta/BMP proteins as therapeutic targets in renal fibrosis. Where have we arrived after 25 years of trials and tribulations? Pharmacol Ther. 2015;156:44–58.

    Article  CAS  Google Scholar 

  16. Vega G, Alarcon S, San Martin R. The cellular and signalling alterations conducted by TGF-beta contributing to renal fibrosis. Cytokine. 2016;88:115–25.

    Article  CAS  Google Scholar 

  17. Kou B, Liu W, Tang X, Kou Q. HMGA2 facilitates epithelial-mesenchymal transition in renal cell carcinoma by regulating the TGF-beta/Smad2 signaling pathway. Oncol Rep. 2018;39:101–8.

    CAS  PubMed  Google Scholar 

  18. Sutariya B, Saraf M. Betanin, isolated from fruits of Opuntia elatior Mill attenuates renal fibrosis in diabetic rats through regulating oxidative stress and TGF-beta pathway. J Ethnopharmacol. 2017;198:432–43.

    Article  CAS  Google Scholar 

  19. Tsai T, Kroehl ME, Smith SM, Thompson AM, Dai IY, Trinkley KE. Efficacy and safety of twice- vs once-daily dosing of lisinopril for hypertension. J Clin Hypertens (Greenwich). 2017;19:868–73.

    Article  CAS  Google Scholar 

  20. Verdura S, Cuyas E, Llorach-Pares L, et al. Silibinin is a direct inhibitor of STAT3. Food Chem Toxicol. 2018;116:161–72.

    Article  CAS  Google Scholar 

  21. Khazim K, Gorin Y, Cavaglieri RC, Abboud HE, Fanti P. The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo. Am J Physiol Renal Physiol. 2013;305:F691–700.

    Article  CAS  Google Scholar 

  22. Wang XT, Sun XJ, Li C, et al. Establishing a cell-based high-content screening assay for TCM compounds with anti-renal fibrosis effects. Evid Based Complement Altern Med. 2018;2018:7942614.

    Google Scholar 

  23. Li H, Cai H, Deng J, et al. TGF-beta-mediated upregulation of Sox9 in fibroblast promotes renal fibrosis. Biochim Biophys Acta Mol Basis Dis. 2018;1864:520–32.

    Article  CAS  Google Scholar 

  24. Higgins SP, Tang Y, Higgins CE, et al. TGF-beta1/p53 signaling in renal fibrogenesis. Cell Signal. 2018;43:1–10.

    Article  CAS  Google Scholar 

  25. March JT, Golshirazi G, Cernisova V, et al. Targeting TGFbeta signaling to address fibrosis using antisense oligonucleotides. Biomedicines. 2018;6:74.

    Article  CAS  Google Scholar 

  26. Branton MH, Kopp JB. TGF-beta and fibrosis. Microbes Infect. 1999;1:1349–65.

    Article  CAS  Google Scholar 

  27. Cho JW, Il KJ, Lee KS. Downregulation of type I collagen expression in silibinin-treated human skin fibroblasts by blocking the activation of Smad2/3-dependent signaling pathways: potential therapeutic use in the chemoprevention of keloids. Int J Mol Med. 2013;31:1148–52.

    Article  CAS  Google Scholar 

  28. Ai W, Zhang Y, Tang QZ, et al. Silibinin attenuates cardiac hypertrophy and fibrosis through blocking EGFR-dependent signaling. J Cell Biochem. 2010;110:1111–22.

    Article  CAS  Google Scholar 

  29. Johnson FL, Patel NSA, Purvis GSD, et al. Inhibition of IkappaB kinase at 24 hours after acute kidney injury improves recovery of renal function and attenuates fibrosis. J Am Heart Assoc. 2017;6:e005092.

    PubMed  PubMed Central  Google Scholar 

  30. Huang J, Chen Z, Li J, et al. Protein kinase CK2alpha catalytic subunit ameliorates diabetic renal inflammatory fibrosis via NF-kappaB signaling pathway. Biochem Pharmacol. 2017;132:102–17.

    Article  CAS  Google Scholar 

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Author notes

  1. Zhongchao Ma and Wenwen Zang contributed equally to this research.

Authors and Affiliations

  1. Department of Nephrology, Liaocheng People’s Hospital, No. 67 West Dongchang Road, Liaocheng, 252000, Shandong, China

    Zhongchao Ma, Wenwen Zang & Huaiguo Wang

  2. Shenxian Zudian Township Hospital, Liaocheng, 252000, Shandong, China

    Xiaojing Wei

Authors
  1. Zhongchao Ma
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  2. Wenwen Zang
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  3. Huaiguo Wang
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  4. Xiaojing Wei
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Correspondence to Huaiguo Wang.

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The authors declare no competing interests in this study.

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All in vivo experiments were performed in accordance with National Institutes of Health guide for the care and use of laboratory animals, following a protocol approved by the Ethics Committees of Liaocheng People’s Hospital.

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13577_2019_314_MOESM1_ESM.jpg

Supplementary material 1 Supplementary Figure 1 In vitro cell model of fibrosis was successfully established. (A) HK-2 cells were treated with 5 ng/ml TGF-β1 for 72 h. Then, expressions of collagen I, MMP9 and α-SMA in cells were measured by RT-qPCR. (B) The protein expressions of collagen I, MMP9 and α-SMA in HK-2 cells were examined by western blot. GAPDH was used as an internal control. The relative protein expression of (C) collagen I, (D) MMP9 and (E) α-SMA normalized to GAPDH was quantified. **P<0.01 vs. control group. Three independent experiments were performed (JPG 533 kb)

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Ma, Z., Zang, W., Wang, H. et al. Silibinin enhances anti-renal fibrosis effect of MK-521 via downregulation of TGF-β signaling pathway. Human Cell 33, 330–336 (2020). https://doi.org/10.1007/s13577-019-00314-9

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  • DOI: https://doi.org/10.1007/s13577-019-00314-9

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