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Differential effects of Smad3 targeting in a murine model of chronic kidney disease

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  • Terese Kellenberger
  • Søren Krag, Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Institute of Clinical Medicine, University of Aarhus, Aarhus, Denmark.
  • ,
  • Carl Christian Danielsen
  • Xiao-Fan Wang, Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC.
  • ,
  • Jens Randel Nyengaard
  • Lea Hougaard Pedersen
  • ,
  • Chuanxu Yang, Department of Molecular Biology, University of Aarhus, Aarhus, Denmark, Danmark
  • Shan Gao, Danmark
  • Lise Wogensen

Transforming growth factor (TGF)-β1 has a pivotal role in the pathogenesis of progressive kidney diseases that are characterized by fibrosis. The main intracellular signaling pathway of TGF-β1 is the Smad system, where Smad2 and Smad3 play a central role in transcriptional regulation of target genes involved in extracellular matrix (ECM) metabolism. This study analyzes the hypothesis that blockade of Smad3 attenuates the development of TGF-β1-driven renal fibrosis. This was examined in vivo in a transgenic model of TGF-β1-induced chronic kidney disease with Smad3 or without Smad3 expression and in vitro in mesangial cells and glomerular endothelial cells with Smad2/3 inhibitors or Smad3-knockdown. Electron microscopy was used for evaluation of morphological changes, real-time polymerase chain reaction for detection of RNA expression, and immunohistochemistry for localization of ECM components. Matrix metalloproteinase (MMP) level was assessed by gelatin zymography electrophoresis and located by in situ zymography. The results show TGF-β1-induced mesangial matrix expansion, tubulointerstitial fibrosis, and tubular basement membrane thickening that are attenuated by Smad3 deletion, whereas TGF-β1-induced glomerular basement membrane thickening is not shown. The amount and distribution profile of MMP-2 may suggest a role of the enzyme herein. We conclude that Smad3 targeting is not exclusively beneficial as Smad3 has diverse transcriptional regulatory effects in different cell types in the kidney.

TidsskriftPhysiological Reports
StatusUdgivet - 1 dec. 2013

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