title: Endothelial cell transforming growth factor-β 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)-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.
authors.affiliation: Department of Internal Medicine, Division of Nephrology & Hypertension, Texas A&M Health Science Center College of Medicine, Temple, Texas 76504, USA.
authors.forename: Valorie L
authors.initials: VL
authors.lastname: Chiasson
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Jones
authors.forename: Shelley E
authors.initials: SE
authors.lastname: Kopriva
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Mahajan
authors.forename: Kristina J
authors.initials: KJ
authors.lastname: Young
authors.forename: Brett M
authors.initials: BM
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052117:Benzodioxoles / Q000494:pharmacology; D065095:Calcineurin Inhibitors; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006818:Hyalin / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000633:toxicity; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism; D016559:Tacrolimus / Q000378:metabolism / Q000633:toxicity*; D022061:Tacrolimus Binding Protein 1A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: C519132:2-(5-benzo(1,3)dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride; D052117:Benzodioxoles; D065095:Calcineurin Inhibitors; D016326:Extracellular Matrix Proteins; D007093:Imidazoles; D007166:Immunosuppressive Agents; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D022061:Tacrolimus Binding Protein 1A; D016559:Tacrolimus