Endothelial cell transforming growth factor- receptor activation causes tacrolimus-induced renal arteriolar hyalinosis. Academic Article uri icon

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)- levels, tacrolimus inhibits calcineurin by binding to FK506-binding protein 12 (FKBP12). FKBP12 alone also inhibits TGF- receptor activation. Here we tested whether tacrolimus binding to FKBP12 removes an inhibition of the TGF- 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- 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- 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- 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- receptor inhibitor SB-505124. Thus, endothelial cell TGF- receptor activation is sufficient to cause vascular remodeling and renal arteriolar hyalinosis.

published proceedings

  • Kidney Int

author list (cited authors)

  • Chiasson, V. L., Jones, K. A., Kopriva, S. E., Mahajan, A., Young, K. J., & Mitchell, B. M.

complete list of authors

  • Chiasson, Valorie L||Jones, Kathleen A||Kopriva, Shelley E||Mahajan, Ashutosh||Young, Kristina J||Mitchell, Brett M

publication date

  • January 1, 2012 11:11 AM