Therapeutic Effects of Tangshen Formula on Diabetic Nephropathy in Rats.

Tingting Zhao,Xi Dong,Xiaoru Huang,Hua Wang,Yumin Wen,Sifan Sun,Meihua Yan,Ping Li,Haojun Zhang,Hui Yao Lan,Zhanjun Jia

doi:10.1371/journal.pone.0147693

Abstract

ObjectiveInflammation 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 MethodsProtective 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.ResultsWe 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.ConclusionsThe 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.

Highlights

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes
We found that Tangshen Formula (TSF) treatment for 20 weeks attenuated diabetic nephropathy (DN) by significantly inhibiting urinary excretion of albumin and renal histological injuries
Further studies revealed that the inhibitory effect of TSF on TGF-β/ Smad3 and NF-κB signaling in DN was associated with inhibition of Smad ubiquitination regulatory factor 2 (Smurf2)-dependent ubiquitin degradation of Smad7

Summary

Introduction

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes It is characterized by glomerular hypertrophy, excessive deposition of extracellular matrix in the mesangium and tubulointerstitium with a slow progression to renal fibrosis accompanied by the development of microalbuminuria and a decline of glomerular filtration rate (GFR) [1, 2]. TGF-β/Smad signaling has been recognized as one of the key pathways in the development of inflammation and fibrosis in many kidney diseases including DN [6, 7]. Smad can negatively regulate NF-κB signaling via induction of IκBα, an inhibitor of NF-κB, thereby blocking IκBα from degradation and preventing the activation of inflammation driven by NF-κB signaling in vivo and in vitro [12, 13]

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