Journal
KIDNEY INTERNATIONAL
Volume 90, Issue 6, Pages 1226-1237Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2016.07.008
Keywords
fibrosis; intracellular translocation; kidney; YB-1
Categories
Funding
- Fritz-Bender-Stiftung
- German Research Foundation (Deutsche Forschungsgemeinschaft) [RA 1927/5-1, RA 740/8-1, OS 196/2-1]
- START-Program (Faculty of Medicine, RWTH, Aachen)
- Interdisciplinary Center for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF) [E7-2, E7-7]
- China Scholarship Council
- [SFBTRR57]
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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 Collal mRNA, thus promoting fibrosis. Conversely, the therapeutic forced nuclear compartmentalization of phosphorylated YB-1 by the small molecule HSc025 mediated repression of the Collal 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.
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