title: Therapeutic nuclear shuttling of YB-1 reduces renal damage and fibrosis.
abstract: Virtually all chronic kidney diseases progress towards tubulointerstitial fibrosis. In vitro, Y-box protein-1 (YB-1) acts as a central regulator of gene transcription and translation of several fibrosis-related genes. However, it remains to be determined whether its pro- or antifibrotic propensities prevail in disease. Therefore, we investigated the outcome of mice with half-maximal YB-1 expression in a model of renal fibrosis induced by unilateral ureteral obstruction. Yb1+/-animals displayed markedly reduced tubular injury, immune cell infiltration and renal fibrosis following ureteral obstruction. The increase in renal YB-1 was limited to a YB-1 variant nonphosphorylated at serine 102 but phosphorylated at tyrosine 99. During ureteral obstruction, YB-1 localized to the cytoplasm, directly stabilizing Col1a1 mRNA, thus promoting fibrosis. Conversely, the therapeutic forced nuclear compartmentalization of phosphorylated YB-1 by the small molecule HSc025 mediated repression of the Col1a1 promoter and attenuated fibrosis following ureteral obstruction. Blunting of these effects in Yb1+/-mice confirmed involvement of YB-1. HSc025 even reduced tubulointerstitial damage when applied at later time points during maximum renal damage. Thus, phosphorylation and subcellular localization of YB-1 determines its effect on renal fibrosis in vivo. Hence, induced nuclear YB-1 shuttling may be a novel antifibrotic treatment strategy in renal diseases with the potential of damage reversal.
authors: Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany.
authors: Jialin
authors: J
authors: Wang
authors: Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany.
authors: Lydia
authors: L
authors: Gibbert
authors: Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany.
authors: Sonja
authors: S
authors: Djudjaj
authors: Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany.
authors: Christina
authors: C
authors: Alidousty
authors: Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany.
authors: Thomas
authors: T
authors: Rauen
authors: Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany.
authors: Uta
authors: U
authors: Kunter
authors: Institute of Organic Chemistry, RWTH Aachen University, Aachen, Germany.
authors: Andreas
authors: A
authors: Rembiak
authors: Institute of Organic Chemistry, RWTH Aachen University, Aachen, Germany.
authors: Dieter
authors: D
authors: Enders
authors: Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
authors: Vera
authors: V
authors: Jankowski
authors: Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany.
authors: Gerald S
authors: GS
authors: Braun
authors: Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany.
authors: Jürgen
authors: J
authors: Floege
authors: Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany.
authors: Tammo
authors: T
authors: Ostendorf
authors: Department of Nephrology and Clinical Immunology, University Hospital RWTH-Aachen, Aachen, Germany. Electronic address: uraffetseder@ukaachen.de.
authors: Ute
authors: U
authors: Raffetseder
mesh_terms: D000466:Alkadienes / Q000627:therapeutic use*; D000818:Animals; D004353:Drug Evaluation, Preclinical; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009400:Nephrosclerosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D014157:Transcription Factors / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D000466:Alkadienes; D014157:Transcription Factors; C546007:HSc025; C541744:Ybx1 protein, mouse
keywords: YB-1; fibrosis; intracellular translocation; kidney