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Endothelial cell transforming growth factor-β receptor activation causes tacrolimus-induced renal arteriolar hyalinosis.
- Source :
-
Kidney International . Oct2012, Vol. 82 Issue 8, p857-866. 10p. - Publication Year :
- 2012
-
Abstract
- Arteriolar hyalinosis is a common histological finding in renal transplant recipients treated with the calcineurin inhibitor tacrolimus; however, the pathophysiologic mechanisms remain unknown. In addition to increasing transforming growth factor (TGF)-β levels, tacrolimus inhibits calcineurin by binding to FK506-binding protein 12 (FKBP12). FKBP12 alone also inhibits TGF-β receptor activation. Here we tested whether tacrolimus binding to FKBP12 removes an inhibition of the TGF-β receptor, allowing ligand binding, ultimately leading to receptor activation and arteriolar hyalinosis. We found that specific deletion of FKBP12 from endothelial cells was sufficient to activate endothelial TGF-β receptors and induce renal arteriolar hyalinosis in these knockout mice, similar to that induced by tacrolimus. Tacrolimus-treated and knockout mice exhibited significantly increased levels of aortic TGF-β receptor activation as evidenced by SMAD2/3 phosphorylation, along with increased collagen and fibronectin expression compared to controls. Treatment of isolated mouse aortas with tacrolimus increased TGF-β receptor activation and collagen and fibronectin expression. These effects were independent of calcineurin, absent in endothelial denuded aortic rings, and could be prevented by the small molecule TGF-β receptor inhibitor SB-505124. Thus, endothelial cell TGF-β receptor activation is sufficient to cause vascular remodeling and renal arteriolar hyalinosis. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00852538
- Volume :
- 82
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Kidney International
- Publication Type :
- Academic Journal
- Accession number :
- 104370658
- Full Text :
- https://doi.org/10.1038/ki.2012.104