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Berberine reduces fibronectin and collagen accumulation in rat glomerular mesangial cells cultured under high glucose condition

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Abstract

Diabetic nephropathy, one of the microvascular complications of diabetes mellitus, is a leading cause of end-stage renal disease. Berberine is one of the main constituents of Coptidis Rhizoma and Cortex Phellodendri. In this study, we investigated the effects of berberine on fibronectin and collagen production, and explored the role of p38MAPK signaling pathway in rat glomerular mesangial cells cultured under high glucose condition. Six groups were divided according to the different experimental conditions: (1) Normal glucose group (NG); (2) Mannitol group (Mannitol); (3) High glucose group (HG); (4) SB203580 treatment group (HG + SB203580); (5) Berberine low dosage group (HG + BBR 30 μM); (6) Berberine high dosage group (HG + BBR 90 μM). Cell proliferation and collagen synthesis were measured by MTT and 3H-proline incorporation assay, respectively. The phospho-p38MAPK, phospho-cAMP response element binding protein (CREB) and fibronectin were detected by western blot analysis. Fibronectin protein expression and collagen synthesis were significantly increased in HG-treated group compared with normal glucose group (P < 0.05). In SB203580 treatment group and two groups of berberine, protein expression of fibronectin and collagen synthesis were obviously decreased compared with HG-treated group (P < 0.05). Berberine significantly decreased protein expression of fibronectin compared with SB203580 treatment group (P < 0.05). Berberine at high dosage significantly decreased collagen synthesis compared with SB203580 treatment group (P < 0.05). Both SB203580 and berberine significantly decreased phospho-p38MAPK and phospho-CREB level compared with HG-treated group (P < 0.05). These results indicated that berberine might inhibit fibronectin and collagen synthesis partly via p38MAPK signal pathway in rat glomerular mesangial cells exposed to high glucose.

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References

  1. Weigert C, Brodbeck K, Brosius FC 3rd, Huber M, Lehmann R, Friess U, Facchin S, Aulwurm S, Haring HU, Schleicher ED, Heilig CW (2003) Evidence for a novel TGF-beta1-independent mechanism of fibronectin production in mesangial cells overexpressing glucose transporters. Diabetes 52:527–535. doi:10.2337/diabetes.52.2.527

    Article  PubMed  CAS  Google Scholar 

  2. Broumand B (2007) Diabetes: changing the fate of diabetics in the dialysis unit. Blood Purif 25:39–47. doi:10.1159/000096396

    Article  PubMed  Google Scholar 

  3. Ayo SH, Radnik RA, Garoni JA, Glass WF 2nd, Kreisberg JI (1990) High glucose causes an increase in extracellular matrix proteins in cultured mesangial cells. Am J Pathol 136:1339–1348

    PubMed  CAS  Google Scholar 

  4. Igarashi M, Wakasaki H, Takahara N, Ishii H, Jiang ZY, Yamauchi T, Kuboki K, Meier M, Rhodes CJ, King GL (1999) Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest 103:185–195. doi:10.1172/JCI3326

    Article  PubMed  CAS  Google Scholar 

  5. Hohenadel D, van der Woude FJ (2004) Gene expression in diabetic nephropathy. Curr Diabetes Rep 4:462–469. doi:10.1007/s11892-004-0057-x

    Article  Google Scholar 

  6. Komers R, Lindsley JN, Oyama TT, Cohen DM, Anderson S (2007) Renal p38 MAP kinase activity in experimental diabetes. Lab Invest 87:548–558

    PubMed  CAS  Google Scholar 

  7. Wilmer WA, Dixon CL, Hebert C (2001) Chronic exposure of human mesangial cells to high glucose environments activates the p38 MAPK pathway. Kidney Int 60:858–871. doi:10.1046/j.1523-1755.2001.060003858.x

    Article  PubMed  CAS  Google Scholar 

  8. Ge B, Gram H, Di Padova F, Huang B, New L, Ulevitch RJ, Luo Y, Han J (2002) MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science 295:1291–1294. doi:10.1126/science.1067289

    Article  PubMed  CAS  Google Scholar 

  9. Singh LP, Andy J, Anyamale V, Greene K, Alexander M, Crook ED (2001) Hexosamine-induced fibronectin protein synthesis in mesangial cells is associated with increases in cAMP responsive element binding (CREB) phosphorylation and nuclear CREB: the involvement of protein kinases A and C. Diabetes 50:2355–2362. doi:10.2337/diabetes.50.10.2355

    Article  PubMed  CAS  Google Scholar 

  10. Issat T, Jakobisiak M, Golab J (2006) Berberine, a natural cholesterol reducing product, exerts antitumor cytostatic/cytotoxic effects independently from the mevalonate pathway. Oncol Rep 16:1273–1276

    PubMed  CAS  Google Scholar 

  11. Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Li Z, Liu J, Jiang JD (2004) Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 10:1344–1351. doi:10.1038/nm1135

    Article  PubMed  CAS  Google Scholar 

  12. Leng SH, Lu FE, Xu LJ (2004) Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacol Sin 25:496–502

    PubMed  CAS  Google Scholar 

  13. Tang LQ, Wei W, Chen LM, Liu S (2006) Effects of berberine on diabetes induced by alloxan and a high-fat/high-cholesterol diet in rats. J Ethnopharmacol 108:109–115. doi:10.1016/j.jep.2006.04.019

    Article  PubMed  CAS  Google Scholar 

  14. Yin J, Gao Z, Liu D, Liu Z, Ye J (2008) Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab 294:E148–E156. doi:10.1152/ajpendo.00211.2007

    Article  PubMed  CAS  Google Scholar 

  15. Kang SW, Adler SG, Lapage J, Natarajan R (2001) p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli. Kidney Int 60:543–552. doi:10.1046/j.1523-1755.2001.060002543.x

    Article  PubMed  CAS  Google Scholar 

  16. Kang MJ, Wu X, Ly H, Thai K, Scholey JW (1999) Effect of glucose on stress-activated protein kinase activity in mesangial cells and diabetic glomeruli. Kidney Int 55:2203–2214. doi:10.1046/j.1523-1755.1999.00488.x

    Article  PubMed  CAS  Google Scholar 

  17. LeHir M, Kriz W (2007) New insights into structural patterns encountered in glomerulosclerosis. Curr Opin Nephrol Hypertens 16:184–191. doi:10.1097/MNH.0b013e3280c8eed3

    Article  PubMed  Google Scholar 

  18. Caramori ML, Mauer M (2003) Diabetes and nephropathy. Curr Opin Nephrol Hypertens 12:273–282. doi:10.1097/00041552-200305000-00008

    Article  PubMed  CAS  Google Scholar 

  19. Price SA, Agthong S, Middlemas AB, Tomlinson DR (2004) Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy: interactions with aldose reductase. Diabetes 53:1851–1856. doi:10.2337/diabetes.53.7.1851

    Article  PubMed  CAS  Google Scholar 

  20. Salahudeen AK, Kanji V, Reckelhoff JF, Schmidt AM (1997) Pathogenesis of diabetic nephropathy: a radical approach. Nephrol Dial Transplant 12:664–668. doi:10.1093/ndt/12.4.664

    Article  PubMed  CAS  Google Scholar 

  21. Schena FP, Gesualdo L (2005) Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 16(Suppl 1):S30–S33. doi:10.1681/ASN.2004110970

    Article  PubMed  CAS  Google Scholar 

  22. Noh H, Ha H, Yu MR, Kang SW, Choi KH, Han DS, Lee HY (2002) High glucose increases inducible NO production in cultured rat mesangial cells. Possible role in fibronectin production. Nephron 90:78–85. doi:10.1159/000046318

    Article  PubMed  CAS  Google Scholar 

  23. Mahimainathan L, Das F, Venkatesan B, Choudhury GG (2006) Mesangial cell hypertrophy by high glucose is mediated by downregulation of the tumor suppressor PTEN. Diabetes 55:2115–2125. doi:10.2337/db05-1326

    Article  PubMed  CAS  Google Scholar 

  24. Yu Y, Lyons TJ (2005) A lethal tetrad in diabetes: hyperglycemia, dyslipidemia, oxidative stress, and endothelial dysfunction. Am J Med Sci 330:227–232. doi:10.1097/00000441-200511000-00005

    Article  PubMed  Google Scholar 

  25. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW et al (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372:739–746. doi:10.1038/372739a0

    Article  PubMed  CAS  Google Scholar 

  26. Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, Nebreda AR (1994) A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78:1027–1037. doi:10.1016/0092-8674(94)90277-1

    Article  PubMed  CAS  Google Scholar 

  27. Adhikary L, Chow F, Nikolic-Paterson DJ, Stambe C, Dowling J, Atkins RC, Tesch GH (2004) Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy. Diabetologia 47:1210–1222. doi:10.1007/s00125-004-1437-0

    Article  PubMed  CAS  Google Scholar 

  28. Suzuki H, Uchida K, Nitta K, Nihei H (2004) Role of mitogen-activated protein kinase in the regulation of transforming growth factor-beta-induced fibronectin accumulation in cultured renal interstitial fibroblasts. Clin Exp Nephrol 8:188–195. doi:10.1007/s10157-004-0297-8

    Article  PubMed  CAS  Google Scholar 

  29. Iordanov M, Bender K, Ade T, Schmid W, Sachsenmaier C, Engel K, Gaestel M, Rahmsdorf HJ, Herrlich P (1997) CREB is activated by UVC through a p38/HOG-1-dependent protein kinase. EMBO J 16:1009–1022. doi:10.1093/emboj/16.5.1009

    Article  PubMed  CAS  Google Scholar 

  30. Pierrat B, Correia JS, Mary JL, Tomas-Zuber M, Lesslauer W (1998) RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen-activated protein kinase (p38alphaMAPK). J Biol Chem 273:29661–29671. doi:10.1074/jbc.273.45.29661

    Article  PubMed  CAS  Google Scholar 

  31. Bowlus CL, McQuillan JJ, Dean DC (1991) Characterization of three different elements in the 5′-flanking region of the fibronectin gene which mediate a transcriptional response to cAMP. J Biol Chem 266:1122–1127

    PubMed  CAS  Google Scholar 

  32. Nahman NS Jr, Rothe KL, Falkenhain ME, Frazer KM, Dacio LE, Madia JD, Leonhart KL, Kronenberger JC, Stauch DA (1996) Angiotensin II induction of fibronectin biosynthesis in cultured human mesangial cells: association with CREB transcription factor activation. J Lab Clin Med 127:599–611. doi:10.1016/S0022-2143(96)90151-1

    Article  PubMed  CAS  Google Scholar 

  33. Wang J, Huang H, Liu P, Tang F, Qin J, Huang W, Chen F, Guo F, Liu W, Yang B (2006) Inhibition of phosphorylation of p38 MAPK involved in the protection of nephropathy by emodin in diabetic rats. Eur J Pharmacol 553:297–303. doi:10.1016/j.ejphar.2006.08.087

    Article  PubMed  CAS  Google Scholar 

  34. Liu W, Liu P, Tao S, Deng Y, Li X, Lan T, Zhang X, Guo F, Huang W, Chen F, Huang H, Zhou SF (2008) Berberine inhibits aldose reductase and oxidative stress in rat mesangial cells cultured under high glucose. Arch Biochem Biophys 475:128–134. doi:10.1016/j.abb.2008.04.022

    Article  PubMed  CAS  Google Scholar 

  35. Liu WH, Hei ZQ, Nie H, Tang FT, Huang HQ, Li XJ, Deng YH, Chen SR, Guo FF, Huang WG, Chen FY, Liu PQ (2008) Berberine ameliorates renal injury in streptozotocin-induced diabetic rats by suppression of both oxidative stress and aldose reductase. Chin Med J (Engl) 121:706–712

    CAS  Google Scholar 

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Acknowledgment

This study was supported by research grant from the Science and Technology Program of Guangdong province, PR China (No. 2008B030301117).

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Authors and Affiliations

  1. Lab of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China

    Weihua Liu, Yanhui Deng, Xuejuan Li, Tian Lan, Xiaoyan Zhang, Heqing Huang & Peiqing Liu

  2. Department of Pharmacology, Guangdong Pharmaceutical University, Guangzhou, 510060, People’s Republic of China

    Futian Tang

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  1. Weihua Liu
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Correspondence to Heqing Huang or Peiqing Liu.

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Weihua Liu and Futian Tang contributed equally to this study.

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Liu, W., Tang, F., Deng, Y. et al. Berberine reduces fibronectin and collagen accumulation in rat glomerular mesangial cells cultured under high glucose condition. Mol Cell Biochem 325, 99–105 (2009). https://doi.org/10.1007/s11010-008-0024-y

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