Download PDF
Planta Med 2014; 80(08/09): 614-621
DOI: 10.1055/s-0034-1368454
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Evidence for the Involvement of JAK/STAT/SOCS Pathway in the Mechanism of Tangshen Formula-Treated Diabetic Nephropathy

Jingjing Hu
1   College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, P. R. China
,
Xuemei Fan
3   Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, P. R. China
,
Xiansheng Meng
1   College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, P. R. China
,
Yiming Wang
3   Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, P. R. China
,
Qionglin Liang
3   Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, P. R. China
,
Guoan Luo
2   State Key Laboratory for Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, P. R. China
3   Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, P. R. China
› Author Affiliations
Further Information

Publication History

received 15 January 2014
revised 17 March 2014

accepted 03 April 2014

Publication Date:
22 May 2014 (online)

Also available at
    Permissions and Reprints

Abstract

Diabetic nephropathy is one of the most significant microvascular complications associated with diabetes. Until now, there is no effective treatment and the gene mechanism of diabetic nephropathy is still unclear. Tangshen formula is a traditional Chinese medicine, and has been shown to have good clinical efficacy in diabetic nephropathy treatment. The objective of this study was to investigate the changes of gene expression profiling and explore the molecular mechanism using a db/db mice model treated by Tangshen formula. After administration for 12 weeks, a microarray was applied to detect the gene expression of db/db mice kidney tissues. Quantitative real-time PCR was used to confirm the differential gene expression and carry out a JAK/STAT/SOCS signaling pathway study. Treatment with Tangshen formula reduced the levels of serum glucose and urinary albumin in db/db mice, and the effects of Tangshen formula on db/db mice were significantly different from the positive control (Losartan potassium tablets) on microarray data. It also showed that the JAK/STAT/SOCS signaling pathway played an important role in the treatment process. The expressions of JAK1, JAK2, and STAT3 were upregulated, and STAT4 was downregulated in Tangshen formula-treated db/db mice. SOCS1, 3, and 7 were all activated, while negative feedback regulated other related genes in the JAK/STAT/SOCS pathway. Our study suggested that Tangshen formula has beneficial effects on diabetic nephropathy treatment via regulating the JAK/STAT/SOCS signaling pathway. This study will help to provide evidence-based recommendations for Tangshen formula clinical treatment.

Key words

Tangshen formula - diabetic nephropathy - microarray - mechanism - JAK/STAT/SOCS

Supporting Information

 

  • References

  • 1 Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, Steffes MW. Nephropathy in diabetes. Diabetes Care 2004; 27: S79-S83
    CrossrefPubMedSearch in Google Scholar
  • 2 Wang H, Mu W, Zhai J, Xing D, Miao S, Wang J, Shang H. The key role of Shenyan Kangfu tablets, a Chinese patent medicine for diabetic nephropathy: study protocol for a randomized, double-blind and placebo-controlled clinical trial. Trials 2013; 14: 165
    CrossrefPubMedSearch in Google Scholar
  • 3 Ma L, Hu J. Clinical observation of treatment of 36 cases of nephrosis diabetes by Western medicine and self-made Tangshen recipe. Beijing J Tradit Chin Med 2005; 24: 263-265
    PubMedSearch in Google Scholar
  • 4 Huang M, Zhu C, Liang QL, Li P, Li J, Wang YM, Luo GA. Effect of Tangshen formula on phospholipids metabolism in diabetic nephropathy patients. Acta Pharm Sin 2011; 46: 780-786
    PubMedSearch in Google Scholar
  • 5 Xia JF, Liang QL, Wang YM, Luo GA. Effect of Tangshen formula on the purine and pyrimidine metabolism of patients with diabetic nephropathy. Chin Tradit Pat Med 2011; 33: 13-17
    PubMedSearch in Google Scholar
  • 6 Zhang H, Li P, Zhao J. Effect of Tangshen formula on expressions of TGF-β1 and MMP-9 of renal tissue in STZ-induced diabetic nephropathy rats. Chin J Integr Tradit Western Nephrol 2009; 10: 290-294
    PubMedSearch in Google Scholar
  • 7 Marrero MB, Banes-Berceli AK, Stern DM, Eaton DC. Role of the JAK/STAT signaling pathway in diabetic nephropathy. Am J Physiol-Renal Physiol 2006; 290: F762-F768
    PubMedSearch in Google Scholar
  • 8 Berthier CC, Zhang H, Schin M, Henger A, Nelson RG, Yee B, Boucherot A, Neusser MA, Cohen CD, Carter-Su C, Argetsinger LS, Rastaldi MP, Brosius FC, Kretzler M. Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes 2009; 58: 469-477
    CrossrefPubMedSearch in Google Scholar
  • 9 Bromberg J, Darnell jr. JE. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 2000; 19: 2468-2473
    CrossrefPubMedSearch in Google Scholar
  • 10 Bromberg JF, Wrzeszczynsk MH, Devga G, Zhao Y, Pestell RG, Albanese C, Darnell jr. JE. Stat3 as an oncogene. Cell 1999; 98: 295-303
    CrossrefPubMedSearch in Google Scholar
  • 11 OʼSullivan LA, Liongue C, Lewis RS, Stephenson SE, Ward AC. Cytokine receptor signaling through the JAK-STAT-SOCS pathway in disease. Mol Immunol 2007; 44: 2497-2506
    CrossrefPubMedSearch in Google Scholar
  • 12 Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signaling and immune regulation. Nat Rev Immunol 2007; 7: 454-465
    CrossrefPubMedSearch in Google Scholar
  • 13 Shuai K, Liu B. Regulation of JAK-STAT signaling in the immune system. Nat Rev Immunol 2003; 3: 900-911
    CrossrefPubMedSearch in Google Scholar
  • 14 Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ. A family of cytokine-inducible inhibitors of signaling. Nature 1997; 387: 917-921
    CrossrefPubMedSearch in Google Scholar
  • 15 Kubo M, Hanada T, Yoshimura A. Suppressors of cytokine signaling and immunity. Nat Immunol 2003; 4: 1169-1176
    CrossrefPubMedSearch in Google Scholar
  • 16 Cooper ME. Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet 1998; 352: 213-219
    CrossrefPubMedSearch in Google Scholar
  • 17 Krolewski AS. Genetics of diabetic nephropathy: evidence for major and minor gene effects. Kidney Int 1999; 55: 1582-1596
    CrossrefPubMedSearch in Google Scholar
  • 18 Nightingale J, Patel S, Suzuki N, Buxton R, Takagi KI, Suzuki J, Sumi Y, Imaizumi A, Mason RM, Zhang Z. Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation. J Am Soc Nephrol 2004; 15: 21-32
    CrossrefPubMedSearch in Google Scholar
  • 19 Wang X, Shaw S, Amiri F, Eaton DC. Marrero MB Inhibition of the Jak/STAT signaling pathway prevents the high glucose-induced increase in TGF-β and fibronectin synthesis in mesangial cells. Diabetes 2002; 51: 3505-3509
    CrossrefPubMedSearch in Google Scholar
  • 20 Liang Y, Jin Y, Li Y. Expression of JAKs/STATs pathway molecules in rat model of rapid focal segmental glomerulosclerosis. Pediatric Nephrol 2009; 24: 1661-1671
    CrossrefPubMedSearch in Google Scholar
  • 21 Shankland SJ. The podocyteʼs response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 2006; 69: 2131-2147
    CrossrefPubMedSearch in Google Scholar
  • 22 Yokota N, Burne-Taney M, Racusen L, Rabb H. Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia–reperfusion injury. Am J Physiol-Renal Physiol 2003; 285: F319-F325
    PubMedSearch in Google Scholar
  • 23 Xu Z, Duan B, Croker BP, Morel L. STAT4 deficiency reduces autoantibody production and glomerulonephritis in a mouse model of lupus. Clin Immunol 2006; 120: 189-198
    CrossrefPubMedSearch in Google Scholar
  • 24 Singh RR, Saxena V, Zang S, Li L, Finkelman FD, Witte DP, Jacob CO. Differential contribution of IL-4 and STAT6 vs. STAT4 to the development of lupus nephritis. J Immunol 2003; 170: 4818-4825
    CrossrefPubMedSearch in Google Scholar
  • 25 Lu TC, Wang ZH, Feng X, Chuang PY, Fang W, Shen Y, He JC. Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy. Kidney Int 2009; 76: 63-71
    CrossrefPubMedSearch in Google Scholar
  • 26 Ortiz-Muñoz G, Lopez-Parra V, Lopez-Franco O, Fernandez-Vizarra P, Mallavia B, Flores C, Gomez-Guerrero C. Suppressors of cytokine signaling abrogate diabetic nephropathy. J Am Soc Nephrol 2010; 21: 763-772
    CrossrefPubMedSearch in Google Scholar
  • 27 Larsen L, Ropke C. Suppressors of cytokine signaling: SOCS. APMIS 2002; 110: 833-844
    CrossrefPubMedSearch in Google Scholar
  • 28 Kile BT, Alexander WS. The suppressors of cytokine signaling (SOCS). Cell Mol Life Sci 2001; 58: 1627-1635
    CrossrefPubMedSearch in Google Scholar
  • 29 Zhang H, Li P, Burczynski FJ, Gong Y, Choy P, Sha H, Li J. Attenuation of Diabetic Nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats with a Combination of Chinese Herbs (Tangshen Formula). Evid Based Complement Alternat Med 2011; 2011: 1-8
    PubMedSearch in Google Scholar