DOI QR코드

DOI QR Code

The Protective Effect of Ginseng Saponin against High Glucose-Induced Secretion of Insulin-Like Growth Factor (IGF)-I in Primary Cultured Rabbit Proximal Tubule Cells

신장 근위세뇨관 세포에서 고포도당에 의한 IGF-I 분비 촉진작용에 있어서 인삼의 차단효과

  • Jung, Ho-Kyoung (Bio-therapy Human Resources Center, animal metical institute Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University) ;
  • Lim, Suel-Ki (Bio-therapy Human Resources Center, animal metical institute Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University) ;
  • Park, Min-Jung (Bio-therapy Human Resources Center, animal metical institute Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University) ;
  • Bae, Chun-Sik (Bio-therapy Human Resources Center, animal metical institute Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University) ;
  • Yoon, Kyung-Chul (Department of Ophthalmology, Chonnam National University Medical School and Hospital) ;
  • Han, Ho-Jae (Bio-therapy Human Resources Center, animal metical institute Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University) ;
  • Park, Soo-Hyun (Bio-therapy Human Resources Center, animal metical institute Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University)
  • 정호경 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학연구소) ;
  • 임슬기 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학연구소) ;
  • 박민정 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학연구소) ;
  • 배춘식 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학연구소) ;
  • 윤경철 (전남대학교 의과대학 안과학교실) ;
  • 한호재 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학연구소) ;
  • 박수현 (전남대학교 수의과대학 바이오치료 산업인력 양성팀, 동물의학연구소)
  • Published : 2009.03.31

Abstract

Diabetic nephropathy is associated with the dysfunction of proximal tubule cells. Insulin-like growth factor 1(IGF-I) has also been considered to play an important role in the development of diabetic nephropathy. Ginsenosides have been used as a remedy for diabetes in Asian countries. Therefore, we examined the preventive effect of ginsenosides against high glucose-induced alteration of IGF-I secretion in the primary cultured proximal tubule cells. In present study, Ginseng saponin (GS) completely blocked high glucose-induced stimulation of IGF-I secretion in proximal tubule cells, whereas panaxatriol (PI) and panaxadiol (PD) partially suppressed. In addition, high glucose stimulated cAMP formation and protein kinase C(PKC) activity from cytosolic to membrane fraction. GS completely prevented high glucose-induced stimulation of cAMP and PKC activity while PT and PD partially did. Furthermore, high glucose-induced stimulation of IGF-I was blocked by the treatment of PKI (protein kinase A inhibitor) and bisindolylmaleimide I (protein kinase C inhibitor). In conclusion, GS prevented high glucose-induced dysfunction of proximal tubule cells.

인삼은 전통적으로 항당뇨 효과가 있는 것으로 보고되고 있다. Insulin-like growth factor (IGF)-I 역시 당뇨병성 신증의 발병 초기에 중요한 역할을 하는 것으로 알려져 있다. 이에 본 연구에서는 신장 근위세뇨관 세포에서 고포도당에 의한 IGF-I 분비에 대한 ginsenoside의 차단 효과 및 이와 관련된 신호전달계를 알아보았다. 결과는 다음과 같다. 고포도당에 의해 증가되었던 IGF-I분비 촉진 작용은 GTS, PD 및 PT 처리 시 차단되었으며, 세포 성장 작용 (세포 비대)에서도 같은 효과를 볼 수 있었다. 아울러 고포도당에 의한 cAMP 및 PKC 활성은 GTS 처리시 현저하게 차단되었으며 PD 및 PT 처리 시 역시 부분적으로 억제되는 것으로 나타났다. 이상의 결과를 볼 때 신장 근위세뇨관 세포에서 ginsenoside는 cAMP 및 PKC 활성 경로를 억제하여 고포도당에 의한 IGFs 분비 작용을 차단하는 것으로 나타났다.

Keywords

References

  1. Locatelli, F., Pozzoni, P. and Del Vecchio, L. : Renal replacement therapy in patients with diabetes and end-stage renal disease. J. Am. Soc. Nephrol. 15, S25-29 (2004) https://doi.org/10.1097/01.ASN.0000093239.32602.04
  2. Thomson, S. C., Vallon, V. and Blantz, R. C. : Kidney function in early diabetes: the tubular hypothesis of glomerular filtration. Am. J. Physiol. Renal Physiol. 286, F8-15 (2004) https://doi.org/10.1152/ajprenal.00208.2003
  3. Yung, S., Lee, C. Y., Zhang, Q., Lau, S. K., Tsang, R. C. and Chan, T. M. : Elevated glucose induction of thrombospondin-1 up-regulates fibronectin synthesis in proximal renal tubular epithelial cells through TGF-beta1 dependent and TGF-beta1 independent pathways. Nephrol. Dial. Transplant. 21, 1504-1513 (2006) https://doi.org/10.1093/ndt/gfl017
  4. Akturk, M., Arslan, M., Altinova, A., Ozdemir, A., Ersoy, R., Yetkin, I., Ayvali, E., Gonen, S. and Toruner, F. : Association of serum levels of IGF-I and IGFBP-1 with renal function in patients with type 2 diabetes mellitus. Growth Horm. IGF. Res. 17, 186-193 (2007) https://doi.org/10.1016/j.ghir.2007.01.007
  5. Tack, I., Elliot, S. J., Potier, M., Rivera, A., Striker, G. E. and Striker, L. J. : Autocrine activation of the IGF-I signaling pathway in mesangial cells isolated from diabetic NOD mice. Diabetes 51, 182-188 (2002) https://doi.org/10.2337/diabetes.51.1.182
  6. Kiefer, D. and Pantuso, T. : Panax ginseng. Am. Fam. Physician 68, 1539-1542 (2003)
  7. Yip, T. T., Lau, C. N., Kong, Y. C., Yung, K. H., Kim, J. H. and Woo, W. S. : Ginsenoside compositions of Panax ginseng C.A. Meyer tissue culture and juice. Am. J. Chin. Med. 13, 89-92 (1985) https://doi.org/10.1142/S0192415X85000137
  8. Waki, I., Kyo, H., Yasuda, M. and Kimura, M. : Effects of a hypoglycemic component of ginseng radix on insulin biosynthesis in normal and diabetic animals. J. Pharmacobiodyn. 5(8), 547-554 (1982) https://doi.org/10.1248/bpb1978.5.547
  9. Xie, J. T., Mehendale, S. R., Wang, A., Han, A. H., Wu, J. A., Osinski, J. and Yuan, C. S. : American ginseng leaf: ginsenoside analysis and hypoglycemic activity. Pharmacol. Res. 49(2), 113-117 (2004) https://doi.org/10.1016/j.phrs.2003.07.015
  10. Cho, W. C., Chung, W. S., Lee, S. K., Leung, A. W., Cheng, C. H. and Yue, K. K. : Ginsenoside Re of Panax ginseng possesses significant antioxidant and antihyperlipidemic efficacies in streptozotocin-induced diabetic rats. Eur. J. Pharmacol. 550(1-3), 173-179 (2006) https://doi.org/10.1016/j.ejphar.2006.08.056
  11. Park, S. H., Shin, S. S. and Han, H. J. : High glucose levels alter angiotensin II induced Ca2+ uptake via PKC and cAMP pathways in renal proximal tubular cells. Kidney Blood Press. Res. 24(2), 84-91 (2001) https://doi.org/10.1159/000054212
  12. Klar, J., Sandner, P., Muller, M. W. and Kurtz, A. : Cyclic AMP stimulates renin gene transcription in juxtaglomerular cells. Pflugers Arch. 444(3), 335-344 (2002) https://doi.org/10.1007/s00424-002-0818-9
  13. Jackson, E. K. and Dubey, R. K. : Role of the extracellular cAMP-adenosine pathway in renal physiology. Am. J. Physiol. Renal Physiol. 281(4), F597-612 (2001) https://doi.org/10.1152/ajprenal.2001.281.4.F597
  14. Kimura, M., Ishizawa, M., Miura, A., Itaya, S., Kanoh, Y., Yasuda, K., Uno, Y., Morita, H. and Ishizuka, T. : Platelet protein kinase C isoform content in type 2 diabetes complicated with retinopathy and nephropathy. Platelets 12(3), 138-143 (2001) https://doi.org/10.1080/09537100120039343
  15. Iori, E., Marescotti, M. C., Vedovato, M., Ceolotto, G., Avogaro, A., Tiengo, A., Del Prato, S. and Trevisan, R. : In situ protein Kinase C activity is increased in cultured fibroblasts from Type 1 diabetic patients with nephropathy. Diabetologia. 46(4), 524-530 (2003) https://doi.org/10.1007/s00125-003-1061-4
  16. Chung, S. D., Alavi, N., Livingston, D., Hiller, S. and Taub, M. : Characterization of primary rabbit kidney cultures that express proximal tubule functions in a hormonally defined medium. J. Cell Biol. 95(1), 118-126 (1982) https://doi.org/10.1083/jcb.95.1.118
  17. Daughaday, W. H. and Rotwein, P. : Insulin-like growth factors I and II. Peptide messenger ribonucleic acid and gene structure serum, and tissue concentrations. Endocr. Rev. 10, 68-91 (1989) https://doi.org/10.1210/edrv-10-1-68
  18. Bowsher, R. R., Lee, W. H., Apathy, J., O'Brien, P. J., Ferguson, A. L. and Henry, D. P. : Measurement of insulin-like growth factor-II in physiological fluids and tissues. I. An improved extraction procedure and radioimmunoassay for human and rat fluids. Endocrinology 128, 805-814 (1991) https://doi.org/10.1210/endo-128-2-805
  19. Sandra, A., Boes, M., Dake, B. L., Stokes, J. B. and Bar, R. S. : Infused IGF-I/IGFBP-3 complex causes glomerular localization of IGF-I in the rat kidney. Am. J. Physiol. 275, E32-E37 (1998)
  20. Wang, S. N., Lapage, J. and Hirschberg, R. : Glomerular ultrafiltration and apical tubular action of IGF-I, TGF-beta, and HGF in nephrotic syndrome. Kidney Int. 56(4), 1247-1251 (1999) https://doi.org/10.1046/j.1523-1755.1999.00698.x
  21. Cummings, E. A., Sochett, E. B., Dekker, M. G., Lawson, M. L. and Daneman, D. : Contribution of growth hormone and IGF-I to early diabetic nephropathy in type 1 diabetes. Diabetes 47(8), 1341-1346 (1998) https://doi.org/10.2337/diabetes.47.8.1341
  22. Samikkannu, T., Thomas, J. J., Bhat, G. J., Wittman, V. and Thekkumkara, T. J. : Acute effect of high glucose on longterm cell growth: a role for transient glucose increase in proximal tubule cell injury. Am. J. Physiol. Renal Physiol. 291(1), F162-F175 (2006) https://doi.org/10.1152/ajprenal.00189.2005
  23. Park, S. H., Choi, H. J., Lee, J. H., Woo, C. H., Kim, J. H. and Han, H. J. : High glucose inhibits renal proximal tubule cell proliferation and involves PKC, oxidative stress, and TGF-beta. Kidney Int. 59(5), 1695-1705 (2001) https://doi.org/10.1046/j.1523-1755.2001.0590051695.x
  24. Cho, W. C., Chung, W. S., Lee, S. K., Leung, A. W., Cheng, C. H. and Yue, K. K. : Ginsenoside Re of Panax ginseng possesses significant antioxidant and antihyperlipidemic efficacies in streptozotocin-induced diabetic rats. Eur. J. Pharmacol. 550(1-3), 173-179 (2006) https://doi.org/10.1016/j.ejphar.2006.08.056
  25. Kang, K. S., Yamabe, N., Kim, H. Y., Park, J. H. and Yokozawa, T. : Therapeutic potential of 20(S)-ginsenoside Rg(3) against streptozotocin-induced diabetic renal damage in rats. Eur. J. Pharmacol. 591(1-3), 266-272 (2008) https://doi.org/10.1016/j.ejphar.2008.06.077
  26. Kim, H. Y., Kang, K. S., Yamabe, N., Nagai, R. and Yokozawa, T. : Protective effect of heat-processed American ginseng against diabetic renal damage in rats. J. Agric. Food Chem. 55, 8491-8497 (2007) https://doi.org/10.1021/jf071770y
  27. Park, K. S., Lee, D. E., Sung, J. H. and Chung, S. H. : Comparisons of antidiabetic effect of panax ginseng on MLD STZ-induced diabetic rats in terms of time of administration. J. Ginseng Res. 26(4), 191-195 (2002) https://doi.org/10.5142/JGR.2002.26.4.191
  28. Inada, A., Kanamori, H., Arai, H., Akashi, T., Araki, M., Weir, G. C. and Fukatsu, A. : A model for diabetic nephropathy: advantages of the inducible cAMP early repressor transgenic mouse over the streptozotocin-induced diabetic mouse. J. Cell Physiol. 215(2), 383-391 (2008) https://doi.org/10.1002/jcp.21316
  29. Wang, J., Huang, H., Liu, P., Tang, F., Qin, J., Huang, W., Chen, F., Guo, F., Liu, W. and Yang, B. : Inhibition of phosphorylation of p38 MAPK involved in the protection of nephropathy by emodin in diabetic rats. Eur. J. Pharmacol. 553(1-3), 297-303 (2006) https://doi.org/10.1016/j.ejphar.2006.08.087
  30. Park, S. H., Choi, H. J., Lee, J. H., Yang, I. S. and Han, H. J. : High glucose stimulates Ca2+ uptake via cAMP and PLC/PKC pathways in primary cultured renal proximal tubule cells. Kidney Blood Press. Res. 24(1), 10-17 (2001) https://doi.org/10.1159/000054200
  31. Koya, D. and King, G. L. : Protein kinase C activation and the development of diabetic complications. Diabetes 47(6), 859-866 (1998) https://doi.org/10.2337/diabetes.47.6.859
  32. Whiteside, C. I. and Dlugosz, J. A. : Mesangial cell protein kinase C isozyme activation in the diabetic milieu. Am. J. Physiol. Renal. Physiol. 282(6), F975-980 (2002) https://doi.org/10.1152/ajprenal.00014.2002
  33. Francki, A., Motamed, K., McClure, T. D., Kaya, M., Murri, C., Blake, D. J., Carbon, J. G. and Sage, E. H. : SPARC regulates cell cycle progression in mesangial cells via its inhibition of IGF-dependent signaling. J. Cell Biochem. 88(4), 802-811 (2003) https://doi.org/10.1002/jcb.10424

Cited by

  1. Effects of Mixed Extract from Lycium chinense, Cordyceps militaris, and Acanthopanax senticosus on Glucose-Regulating Enzymes of HepG2 in Hyperglycemic Conditions vol.39, pp.9, 2010, https://doi.org/10.3746/jkfn.2010.39.9.1257