title: Y-box binding protein-1 mediates profibrotic effects of calcineurin inhibitors in the kidney.
abstract: The immunosuppressive calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus are widely used in transplant organ recipients, but in the kidney allograft, they may cause tubulointerstitial as well as mesangial fibrosis, with TGF-β believed to be a central inductor. In this study, we report that the cold-shock protein Y-box binding protein-1 (YB-1) is a TGF-β independent downstream effector in CsA- as well as in tacrolimus- but not in rapamycin-mediated activation of rat mesangial cells (rMCs). Intracellular content of YB-1 is several-fold increased in MCs following CNI treatment in vitro and in vivo in mice. This effect ensues in a time-dependent manner, and the operative concentration range encompasses therapeutically relevant doses for CNIs. The effect of CNI on cellular YB-1 content is abrogated by specific blockade of translation, whereas retarding the transcription remains ineffective. The activation of rMCs by CNIs is accomplished by generation of reactive oxygen species. In contrast to TGF-β-triggered reactive oxygen species generation, hydrogen peroxide especially could be identified as a potent inductor of YB-1 accumulation. In line with this, hindering TGF-β did not influence CNI-induced YB-1 upregulation, whereas ERK/Akt pathways are involved in CNI-mediated YB-1 expression. CsA-induced YB-1 accumulation results in mRNA stabilization and subsequent generation of collagen. Our results provide strong evidence for a CNI-dependent induction of YB-1 in MCs that contributes to renal fibrosis via regulation of its own and collagen translation.
authors: Department of Nephrology and Clinical Immunology, University Hospital Rheinisch-Westfälische Technische Hochschule-Aachen, Aachen 52057, Germany.
authors: Lydia
authors: L
authors: Hanssen
authors: Björn C
authors: BC
authors: Frye
authors: Tammo
authors: T
authors: Ostendorf
authors: Christina
authors: C
authors: Alidousty
authors: Sonja
authors: S
authors: Djudjaj
authors: Peter
authors: P
authors: Boor
authors: Thomas
authors: T
authors: Rauen
authors: Jürgen
authors: J
authors: Floege
authors: Peter R
authors: PR
authors: Mertens
authors: Ute
authors: U
authors: Raffetseder