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Berberine ameliorates renal injury by regulating G proteins-AC- cAMP signaling in diabetic rats with nephropathy

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Abstract

Diabetic nephropathy (DN) is a progressive kidney disease that is caused by injury to glomerulus and glomerular mesangial cells (MCs) proliferation play a critical role in the pathogenesis of DN. The current studies were undertaken to investigate the protective effects and the possible molecular mechanism of berberine on streptozotocin (STZ)-induced DN rats. Male Wistar rats were randomly assigned to normal control and DN groups of comparable age. Three DN groups received 50, 100 and 200 mg/kg of berberine for 8 weeks via daily intragastrically, respectively. The G proteins-adenylyl cyclase (AC)-cAMP signaling pathway and glomerular MCs proliferation were examined in STZ-induced diabetic rat kidney. Enhanced MCs proliferation and remarkable renal injury were concomitant with activation of Gαi and inhibition of Gαs and cAMP in DN model group. Berberine treatment for 8 weeks abolished the above changes by upregulating the expression of Gαs protein and downregulating the expression of Gαi protein, increasing cAMP level, and inhibiting MCs proliferation compared with model group. Taken together, for the first time, these results demonstrated that berberine can relieve renal injury in DN rats through mediating G proteins-AC-cAMP signaling pathway and inhibiting the abnormal proliferation of MCs by increasing cAMP level, suggesting that berberine could be a potential therapeutic agent for the treatment of DN.

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Abbreviations

G proteins:

Heterotrimeric GTP-binding proteins

DN:

Diabetic nephropathy

STZ:

Streptozotocin

ECM:

Extracellular matrix

GBM:

Glomerular basement membrane

Camp:

Adenosine 3-,5- monophosphate

AC:

Adenylate cyclase

TGF-β1 :

Transforming growth factor-beta1

FN:

Fibronectin

CTGF:

Connective tissue factor

FBG:

Fasting blood glucose

References

  1. Guilbert JJ (2006) The World Health Report 2006: working together for health. Educ Health (Abingdon) 19:385–387

    Article  Google Scholar 

  2. Dronavalli S, Duka I, Bakris GL (2008) The pathogenesis of diabetic nephropathy. Nat Clin Pract Endocrinol Metab 4:444–452

    Article  PubMed  CAS  Google Scholar 

  3. Kanwar YS, Sun L, Xie P et al (2011) A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol 6:395–423

    Article  PubMed  CAS  Google Scholar 

  4. Reutens AT, Atkins RC (2011) Epidemiology of diabetic nephropathy. Contrib Nephrol 170:1–7

    Article  PubMed  Google Scholar 

  5. Kobayashi T, Okada H, Inoue T et al (2006) Tubular expression of connective tissue growth factor correlates with interstitial fibrosis in type 2 diabetic nephropathy. Nephrol Dial Transplant 21:548–549

    Article  PubMed  Google Scholar 

  6. Guha M, Xu ZG, Tung D et al (2007) Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB J 21(12):3355–3368

    Article  PubMed  CAS  Google Scholar 

  7. Umezono T, Toyoda M, Kato M et al (2006) Glomerular expression of CTGF, TGF-beta 1 and type IV collagen in diabetic nephropathy. J Nephrol 19(6):751–757

    PubMed  CAS  Google Scholar 

  8. Zhang Z, Kundu GC, Yuan CJ et al (1997) Severe fibronectin-deposit renal glomerular disease in mice lacking uteroglobin. Science 276:1408–1412

    Article  PubMed  CAS  Google Scholar 

  9. Striker GE, Peten EP, Carome MA et al (1993) The kidney disease of diabetes mellitus (KDDM): a cell and molecular biology approach. Diabetes Metab Rev 9:37–56

    Article  PubMed  CAS  Google Scholar 

  10. Van Nieuwenhoven FA, Jensen LJ, Flyvbjerg A et al (2005) Imbalance of growth factor signalling in diabetic kidney disease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point? Nephrol Dial Transplant 20:6–10

    Article  PubMed  Google Scholar 

  11. Hoffman BB, Sharma K, Ziyadeh FN (1998) Potential role of TGF-βin diabetic nephropathy. Miner Electrolyte Metab 24:190–196

    Article  PubMed  CAS  Google Scholar 

  12. Goldschmeding R, Aten J, Ito Y et al (2000) Connective tissue growth factor: just another factor in renal fibrosis? Nephrol Dial Transplant 15:296–299

    Article  PubMed  CAS  Google Scholar 

  13. Boor P, Sebeková K, Ostendorf T et al (2007) Treatment targets in renal fibrosis. Nephrol Dial Transplant 22:3391–3407

    Article  PubMed  CAS  Google Scholar 

  14. Gupta S, Clarkson MR, Duggan J et al (2000) Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis. Kidney Int 58:1389–1399

    Article  PubMed  CAS  Google Scholar 

  15. Wahab NA, Yevdokimova N, Weston BS et al (2001) Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. Biochem J 359:77–87

    Article  PubMed  CAS  Google Scholar 

  16. Yokoi H, Mukoyama M, Nagae T et al (2004) Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J Am Soc Nephrol 15:1430–1440

    Article  PubMed  CAS  Google Scholar 

  17. Giunti S, Barit D, Cooper ME (2006) Diabetic nephropathy: from mechanisms to rational therapies. Minerva Med 97:241–262

    PubMed  CAS  Google Scholar 

  18. Gilman AG (1987) G-proteins: transducers of receptor generated signals. Annu Rev Biochem 56:615–649

    Article  PubMed  CAS  Google Scholar 

  19. Bourne HR, Sanders DA, McCormick F (1990) The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348:125–132

    Article  PubMed  CAS  Google Scholar 

  20. Neer EJ, Heterotrimeric G (1995) Proteins: organizers of transmembrane signals. Cell 80:249–257

    Article  PubMed  CAS  Google Scholar 

  21. Jang IS, Juhnn YS (2001) Adaptation of cAMP signaling system in SH-SY5Y neuroblastoma cells following expression of a constitutively active stimulatory G protein alpha, Q227L Gsalpha. Exp Mol Med 33(1):37–45

    Article  PubMed  CAS  Google Scholar 

  22. Salazar NC, Chen J, Rockman HA (2007) Cardiac GPCRs: GPCR signaling in healthy and failing hearts. Biochim Biophys Acta 1768:1006–1018

    Article  PubMed  CAS  Google Scholar 

  23. Yin J, Xing H, Ye J (2008) Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism 57:712–717

    Article  PubMed  CAS  Google Scholar 

  24. Yin J, Gao Z, Liu D et al (2008) Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab 294:E148–E156

    Article  PubMed  CAS  Google Scholar 

  25. Singh J, Kakkar P (2009) Antihyperglycemic and antioxidant effect of Berberis aristata root extract and its role in regulating carbohydrate metabolism in diabetic rats. J Ethnopharmacol 123:22–26

    Article  PubMed  Google Scholar 

  26. Wang Y, Champbell T, Perry B (2011) Hypoglycemic and insulin-sensitizing effects of berberine in high-fat diet- and streptozotocin-induced diabetic rats. Metabolism 60(2):298–305

    Article  PubMed  CAS  Google Scholar 

  27. Liu WH, Hei ZQ, Nie H et al (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 

  28. Liu W, Liu P, Tao S et al (2008) Berberine inhibits aldose reductase and oxidative stress in rat mesangial cells cultured under high glucose. Arch Biochem Biophys 475:128–134

    Article  PubMed  CAS  Google Scholar 

  29. Liu W, Tang F, Deng Y et al (2009) Berberine reduces fibronectin and collagen accumulation in rat glomerular mesangial cells cultured under high glucose condition. Mol Cell Biochem 325:99–105

    Article  PubMed  CAS  Google Scholar 

  30. Liu S, Tang LQ, Chen LM (2004) Study on extraction technology of berberine from Rhizoma coptidis by the method of orthogonal-test optimization. China Pharm 15:18–20

    Google Scholar 

  31. Xu SY, Bian RL, Chen X (2003) Experimental methods in pharmacology. People health publishing, Beijing, p 585

    Google Scholar 

  32. Zhou R, Guo JJ, Yin CM, et al (2003) Clinical observations of Xiaoke Wan in treatment of type 2 diabetic patients (Qi and Yin deficiency zheng). Zhongguo YaoWu Yu Lin Chuang 3:131–132 (Chinese)

  33. Zhang HZ (1999) Clinical observation into Xiaoke Wan in the treatment of 86 cases of type 2 diabetic patients. Zhong Yi Yao Yan Jiu 15:19–21 (Chinese)

    Google Scholar 

  34. Itoh Y, Imamura S, Yamamoto K et al (2002) Changes of endothelin in streptozotocin-induced diabetic rats: effects of an angiotensin converting enzyme inhibitor, enalapril maleate. J Endocrinol 175(1):233–239

    Article  PubMed  CAS  Google Scholar 

  35. Fujiwara Y, Kitamura E, Ochi S et al (1991) Isotopic measurement of glomerular intracapillary volume as a quantitative index for mesangial cell contractility. Contrib Nephrol 95:12–21

    PubMed  CAS  Google Scholar 

  36. Wolf G, Ziyadeh FN (1999) Molecular mechanism of diabetic renal hypertrophy. Kidney Int 56:393–405

    Article  PubMed  CAS  Google Scholar 

  37. Lu SS, Yu YL, Zhu HJ et al (2009) Berberine promotes glucagon-like peptide–1 (7–36) amide secretion in streptozotocin-induced diabetic rats. J Endocrinol 200:159–165

    Article  PubMed  CAS  Google Scholar 

  38. Schena FP (2005) Gesualdo L Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 16(Suppl 1):S30–S33

    Article  PubMed  CAS  Google Scholar 

  39. Ichinose K, Kawasaki E, Eguchi K (2007) Recent advancement of understanding pathogenesis of type 1 diabetes and potential relevance to diabetic nephropathy. Am J Nephrol 27:554–564

    Article  PubMed  CAS  Google Scholar 

  40. Liu Y (2006) Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidndy Int 69:213–217

    Article  CAS  Google Scholar 

  41. Ruiz-Torres MP, Lopez-Ongil S, Griera M et al (2005) The accumulation of extracellular matrix in the kidney: consequences on cellular function. J Nephrol 18:334–340

    PubMed  CAS  Google Scholar 

  42. Molitch ME, DeFronzo RA, Franz MJ et al (2004) American Diabetes Association. Nephropathy in diabetes. Diabetes Care 27:S79–S83

    Article  PubMed  Google Scholar 

  43. Chen S, Hong SW, Iglesias-de la Cruz MC et al (2001) The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy. Renal Fail 23:471–481

    Article  CAS  Google Scholar 

  44. Ziyadeh FN, Sharma K, Ericksen M et al (1994) Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor beta. J Clin Invest 93:536–542

    Article  PubMed  CAS  Google Scholar 

  45. Murphy M, Docherty NG, Griffin B et al (2008) IHG-1 amplifies TGF-beta 1 signaling and is increased in renal fibrosis. J Am Soc Nephrol 19:1672–1680

    Article  PubMed  CAS  Google Scholar 

  46. Abdel WN, Mason RM (2004) Connective tissue growth factor and renal diseases: some answers, more questions. Curr Opin Nephrol Hypertens 13:53–58

    Article  Google Scholar 

  47. Mason RM, Wahab NA (2003) Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol 14:1358–1373

    Article  PubMed  CAS  Google Scholar 

  48. Liu W, Zhang X, Liu P et al (2010) Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury. Eur J Pharmacol 638(1–3):150–155

    Article  PubMed  CAS  Google Scholar 

  49. Kurogi Y (2003) Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease. Med Res Rev 23:15–31

    Article  PubMed  CAS  Google Scholar 

  50. Li X, Liu W, Wang Q (2009) Huang, et al. Emodin suppresses cell proliferation and fibronectin expression via p38MAPK pathway in rat mesangial cells cultured under high glucose. Mol Cell Endocrinol 307:157–162

    Article  PubMed  CAS  Google Scholar 

  51. Hashim S, Liu YY, Wang R et al (2002) Streptozotocin induced diabetes impairs G-protein linked signal transduction in vascular smooth muscle. Mol Cell Biochem 240:57–65

    Article  PubMed  CAS  Google Scholar 

  52. Hashim S, Li Y, Nagakura A, Takeo S et al (2004) Modulation of G-protein expression and adenylyl cyclase signaling by high glucose in vascular smooth muscle. Cardiovasc Res 63:709–718

    Article  PubMed  CAS  Google Scholar 

  53. Zheng XL, Guo J, Wang HY, Malbon CC (1998) Expression of constitutively activated Gialpha2 in vivo ameliorates streptozotocin-induced diabetes. J Biol Chem 273:23649–23651

    Article  PubMed  CAS  Google Scholar 

  54. Li Y, Descorbeth M, Anand-Srivastava MB (2008) Role of oxidative stress in high glucose-induced decreased expression of Giα proteins and adenylyl cyclase signaling in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 294(6):H2845–H2854

    Article  PubMed  CAS  Google Scholar 

  55. Stryer L, Bourne HR (1986) G proteins: a family of signal transducers. Annu Rev Cell Biol 2:391–419

    Article  PubMed  CAS  Google Scholar 

  56. Spiegel AM (1987) Signal transduction by guanine nucleotide binding proteins. Mol Cell Endocrinol 49:1–16

    Article  PubMed  CAS  Google Scholar 

  57. Dumont JE, Jauniaux JC, Roger PP (1989) The cyclic AMP-mediated stimulation of cell proliferation. Trends Biochem Sci 14:67–71

    Article  PubMed  CAS  Google Scholar 

  58. Li X, Zarinetchi F, Schrier RW et al (1995) Inhibition of MAP kinase by prostaglandin E2 and forskolin in rat renal mesangial cells. Am J Physiol 269:C986–C991

    PubMed  CAS  Google Scholar 

  59. Hashim S, Li Y, Anand-Srivastava MB (2006) G Protein-linked cell signaling and cardiovascular functions in diabetes/hyperglycemia. Cell Biochem Biophys 44(1):51–64

    Article  PubMed  CAS  Google Scholar 

  60. Tang LQ, Lv F, Liu S et al (2011) Effect of berberine on expression of transforming growth factor-beta1 and type IV collagen proteins in mesangial cells of diabetic rats with nephropathy. Zhongguo Zhong Yao Za Zhi 36:3494–3497 (Chinese)

    Google Scholar 

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Acknowledgments

This Project was supported by the National Natural Science Foundation of China (Nos. 81073109, 81102864) and Natural Science Foundation of Anhui Province (China, No. 090413106). We would like to extend our appreciation to Wei Wei and the staff at the School of Pharmacy, Anhui College of Traditional Chinese Medicine for their technical support.

Conflict of interest

There are no competing financial interests in relation to the work.

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Authors and Affiliations

  1. Department of Pharmacy, Affiliated Anhui Provincial Hospital, Anhui Medical University, Hefei, 230001, Anhui, People’s Republic of China

    Li Qin Tang, Ling Na Zhu, Fei Lv, Sheng Liu & Shan Tang Zhang

  2. Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, People’s Republic of China

    Feng Ling Wang

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  1. Li Qin Tang
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  2. Feng Ling Wang
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Correspondence to Li Qin Tang.

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Tang, L.Q., Wang, F.L., Zhu, L.N. et al. Berberine ameliorates renal injury by regulating G proteins-AC- cAMP signaling in diabetic rats with nephropathy. Mol Biol Rep 40, 3913–3923 (2013). https://doi.org/10.1007/s11033-012-2468-0

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