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

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.

SUBMITTER: Chiasson VL

PROVIDER: S-EPMC3396764 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Chiasson Valorie L VL Jones Kathleen A KA Kopriva Shelley E SE Mahajan Ashutosh A Young Kristina J KJ Mitchell Brett M BM

Kidney international 20120411 8

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, allow ...[more]

PMID: 22495293

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Dataset Information

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

Publications

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

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