Astragaloside IV inhibits renal tubulointerstitial fibrosis by blocking TGF-β/Smad signaling pathway in vivo and in vitro.

Abstract

Astragaloside IV (AS-IV) is a major active ingredient from Radix astragali, which has been considered as a renoprotective agent; however, its molecular mechanisms are unclear. Thus, we designed to investigate the renoprotective effects and mechanisms of AS-IV in rat model of renal fibrosis induced by unilateral ureteral obstruction (UUO) in vivo and TGF-β1-stimulated rat renal fibroblasts (NRK-49F) in vitro. Sprague-Dawley rats were randomly divided into six groups: sham operation, UUO, UUO/AS-IV (3.3, 10, 33 mg·kg(-1)·d(-1)), and UUO/enalapril (4 mg·kg(-1)·d(-1)). Renal function, tubulointerstitial damage index score, extracellular matrix (ECM) deposition, and the expressions of TGF-β1, connective tissue growth factor (CTGF), α-SMA, fibronectin, collagen I, III, Smad2/3, phosphorylated-Smad2/3, and Smad7 were measured. In addition, the expressions of CTGF, α-SMA, fibronectin, collagen I, III, Smad2/3, phosphorylated-Smad2/3, and Smad7 were measured in TGF-β1-stiumlated NRK-49F cell line. AS-IV significantly decreased UUO-induced renal fibrosis and functional impairment, which are associated with inhibition of TGF-β1, CTGF, α-SMA, and collagen matrix expression, and a decrease in serum creatinine and urea nitrogen. The renoprotective effects of AS-IV on fibrosis were associated with up-regulation of Smad7, thereby blocking up-regulations of TGF-β1, CTGF, and α-SMA, and activation of phosphorylated-Smad2/3. These effects were further conformed in NRK-49F cell line stimulated by TGF-β1. Moreover, knockdown of Smad7 gene in NRK-49F cells was able to prevent AS-IV-induced inhibition to Smad2/3 signaling activation, expression of CTGF, α-SMA, and ECM proteins in response to TGF-β1. Renal tubulointerstitial fibrosis was attenuated by treatment with AS-IV, which was closely related to induction of Smad7, thereby inhibiting TGF-β/Smad signaling.

• Authors: Li Wang, Yang-Feng Chi, Ze-Ting Yuan, Wen-Chao Zhou, Pei-Hao Yin, Xue-Mei Zhang, Wen Peng, Hui Cai
• Journal: Experimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 239 Issue 10 Pg. 1310-24 (Oct 2014) ISSN: 1535-3699 [Electronic] England
• PMID: 24879422 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2014 by the Society for Experimental Biology and Medicine.

Chemical References

• Saponins
• Smad7 Protein
• Smad7 protein, rat
• Transforming Growth Factor beta
• Triterpenes
• astragaloside A

Topics

• Animals
• Disease Models, Animal
• Fibrosis (pathology, prevention & control)
• Gene Expression Profiling
• Kidney (drug effects, pathology)
• Kidney Diseases (pathology, prevention & control)
• Kidney Function Tests
• Rats, Sprague-Dawley
• Saponins (administration & dosage)
• Severity of Illness Index
• Signal Transduction (drug effects)
• Smad7 Protein (biosynthesis)
• Transforming Growth Factor beta (antagonists & inhibitors)
• Triterpenes (administration & dosage)