MISC

2003年11月

Targeted disruption of TGF-beta 1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction

JOURNAL OF CLINICAL INVESTIGATION
  • M Sato
  • ,
  • Y Muragaki
  • ,
  • S Saika
  • ,
  • AB Roberts
  • ,
  • A Ooshima

112
10
開始ページ
1486
終了ページ
1494
記述言語
英語
掲載種別
DOI
10.1172/JCI200319270
出版者・発行元
AMER SOC CLINICAL INVESTIGATION INC

Tubulointerstitial fibrosis is the final common result of a variety of progressive injuries leading to chronic renal failure. Transforming growth factor-beta (TGF-beta) is reportedly upregulated in response to injurious stimuli such as unilateral ureteral obstruction (UUO), causing renal fibrosis associated with epithelial-mesenchymal transition (EMT) of the renal tubules and synthesis of extracellular matrix. We now show that mice lacking Smad3 (Smad3(ex8/ex8)) a key signaling intermediate downstream of the TGF-beta receptors, are protected against tubulointerstitial fibrosis following UUO as evidenced by blocking of EMT and abrogation of monocyte influx and collagen accumulation. Culture of primary renal tubular epithelial cells from wild-type or Smad3-null mice confirms that the Smad3 pathway is essential for TGF-beta1-induced EMT and autoinduction of TGF-beta1. Moreover, mechanical stretch of the cultured epithelial cells, mimicking renal tubular distention due to accumulation of urine after UUO induces EMT following Smad3-mediated upregulation of TGF-beta1. Exogenous bone marrow monocytes accelerate EMT of the cultured epithelial cells and renal tubules in the obstructed kidney after UUO dependent on Smad3 signaling. Together the data demonstrate that the Smad3 pathway is central to the pathogenesis of interstitial fibrosis and suggest that inhibitors of this pathway may have clinical application in the treatment of obstructive nephropathy.

リンク情報
DOI
https://doi.org/10.1172/JCI200319270
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000186580400007&DestApp=WOS_CPL
ID情報
  • DOI : 10.1172/JCI200319270
  • ISSN : 0021-9738
  • Web of Science ID : WOS:000186580400007

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