Therapeutic nuclear shuttling of YB-1 reduces renal damage and fibrosis. 
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.