Endothelial cell transforming growth factor-? receptor activation causes tacrolimus-induced renal arteriolar hyalinosis

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.


Authors: Valorie L Chiasson, Kathleen A Jones, Shelley E Kopriva, Ashutosh Mahajan, Kristina J Young and Brett M Mitchell

Reference: Kidney International 82: 857-866; Published online, 11 April 2012; doi:10.1038/ki.2012.104

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