Therapeutic Effects of Tangshen Formula on Diabetic Nephropathy in Rats

PLoS One. 2016 Jan 25;11(1):e0147693. doi: 10.1371/journal.pone.0147693. eCollection 2016.

Abstract

Objective: Inflammation and fibrosis are essential promoters in the pathogenesis of diabetic nephropathy (DN) in type 2 diabetes. The present study examined the anti-inflammation and anti-fibrosis effect of Tangshen Formula (TSF), a traditional Chinese medicine, on DN.

Research design and methods: Protective role of TSF in DN was examined in a rat model of type 2 DN that was established by high-fat diet-fed and low-dose-streptozotocin injection. TSF was suspended in 0.5% CMC-Na solution and delivered by oral gavage at a dosage of 1.67g/Kg body weight/day. The therapeutic effects and mechanisms of TSF on diabetic kidney injury were examined.

Results: We found that TSF treatment for 20 weeks attenuated DN by significantly inhibiting urinary excretion of albumin and renal histological injuries. These beneficial effects were associated with an inactivation of NF-κB signaling, thereby blocking the upregulation of pro-inflammatory cytokines (IL-1β, TNFα), chemokine (MCP-1), and macrophage infiltration in the TSF-treated rats with type 2 DN. In addition, TSF treatment also inactivated TGF-β/Smad3 signaling and therefore suppressed renal fibrosis including expressions of fibronectin, collagen I, and collagen IV. Further studies revealed that the inhibitory effect of TSF on TGF-β/Smad3 and NF-κB signaling in DN was associated with inhibition of Smurf2-dependent ubiquitin degradation of Smad7.

Conclusions: The present study reveals that TSF has therapeutic potential for type 2 DN in rats. Blockade of NF-κB-driven renal inflammation and TGF-β/Smad3-mediated renal fibrosis by preventing the Smurf2-mediated Smad7 degradation pathway may be mechanisms through which TSF inhibits type 2 DN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CCL2 / metabolism
  • Cytokines / metabolism
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Drugs, Chinese Herbal / pharmacology
  • Drugs, Chinese Herbal / therapeutic use*
  • Interleukin-1beta / metabolism
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Medicine, Chinese Traditional
  • NF-kappa B / metabolism
  • Rats
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Ccl2 protein, rat
  • Chemokine CCL2
  • Cytokines
  • Drugs, Chinese Herbal
  • Interleukin-1beta
  • NF-kappa B
  • Tumor Necrosis Factor-alpha

Grant support

This work was supported by grants from the National Natural Science Foundation of China (No: 81173422 and 81130066 to PL, No: 81473526 to TTZ, No: 81373795 to HJZ, No: 81302942 to MHY), http://www.nsfc.gov.cn/; Beijing Natural Science Foundation (No: 7142143 to TTZ), http://www.bjnsf.org/; the China-International S & T Cooperation (No: 2011DFA31860 to PL), the Major State Basic Research Development Program of China (973 program, 2012CB517705 to HYL), http://www.most.gov.cn/; the Research Grant Council of Hong Kong (CUHK3/CRF/12R to HYL), http://www.most.gov.cn/; The Focused Investment Scheme A from Chinese University of Hong Kong (HYL), http://www.cuhk.edu.hk/chinese/index.html, and the China–Japan Friendship Hospital Youth Science and Technology Excellence Project. Award Number: 2015-QNYC-B-09. Recipient: Ting Ting Zhao, Ph.D.