期刊
EXPERIMENTAL BIOLOGY AND MEDICINE
卷 239, 期 10, 页码 1310-1324出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/1535370214532597
关键词
Astragaloside IV; renal tubulointerstitial fibrosis; unilateral ureteral obstruction; TGF-beta/Smad signaling pathway
资金
- General Medicine of Key Discipline Construction Project, State Administration of Traditional Chinese Medicine of the People's Republic of China
- Leading Academic Discipline Project of State Administration of Traditional Chinese Medicine of China, Talent Project of Integrative Medicine of Shanghai Municipal Health Bureau [ZYSNXD012-RC-ZXY]
- Key Medical Discipline Project of Shanghai Municipal Health Bureau [ZK2012A34]
- Independent Innovation Research Fund of Putuo District Science and Technology Committee [2012PTKW002]
- Department of Veteran Affairs MERIT Award [5I01BX000994]
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-beta 1-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, 33mg.kg(-1).d(-1)), and UUO/enalapril (4mg.kg(-1).d(-1)). Renal function, tubulointerstitial damage index score, extracellular matrix (ECM) deposition, and the expressions of TGF-beta 1, connective tissue growth factor (CTGF), alpha-SMA, fibronectin, collagen I, III, Smad2/3, phosphorylated-Smad2/3, and Smad7 were measured. In addition, the expressions of CTGF, alpha-SMA, fibronectin, collagen I, III, Smad2/3, phosphorylated-Smad2/3, and Smad7 were measured in TGF-beta 1-stiumlated NRK-49F cell line. AS-IV significantly decreased UUO-induced renal fibrosis and functional impairment, which are associated with inhibition of TGF-beta 1, CTGF, alpha-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-beta 1, CTGF, and alpha-SMA, and activation of phosphorylated-Smad2/3. These effects were further conformed in NRK-49F cell line stimulated by TGF-beta 1. 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, alpha-SMA, and ECM proteins in response to TGF-beta 1. Renal tubulointerstitial fibrosis was attenuated by treatment with AS-IV, which was closely related to induction of Smad7, thereby inhibiting TGF-beta/Smad signaling.
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