Y-box-binding protein (YB-1) in murine models of hepatic and renal fibrosis

Background: The Y-box binding protein-1 (YB-1) exerts pleiotropic functions in gene transcription and in translation, e.g. of fibrosis-related genes. Recent in vitro findings point to opposite regulatory effects on fibrogenesis by YB-1 that depend on its subcellular localization. YB-1 might even accomplish opposite functions on gene transcription and mRNA translation of the same gene product, e.g. that of type I collagen (Col1A), a major constituent of the extracellular matrix (ECM) [1]. This led us to in vivo investigations that analyze the outcome of half-maximal YB-1 depletion in a model of liver fibrosis (bile duct ligation (BDL)) and compared the results to renal fibrosis, investigated by unilateral ureteral obstruction (UUO). Additionally, the impact of BDL on kidney damage was assessed.

Material and Methods: BDL (for 2 weeks) and UUO (for 5 days) was performed in wildtype (wt) and heterozygous YB-1 knockout (Yb-1+/-) mice that are characterized by half-normal YB-1 content on mRNA and protein level [2,3]. YB-1-/- mice are not viable. Parameters of hepatic and renal fibrosis were determined by serum parameters, IHC, qRT-PCR and Western blot analyses. Comparative reporter gene expression studies were performed in primary hepatic cells isolated from Yb-1+/- and wt mice.

Results: Hepatic serum parameters (e.g. alkaline phosphatase, ALT) and expression of ECM proteins such as type I collagen (Col1A) were significantly reduced in Yb-1+/- compared to wt mice. Col1A promoter activation in primary wt hepatocytes following TGF-β challenge was weak and further diminished when cells were obtained from Yb-1+/- mice. In line with this, half-maximal expression of YB-1 resulted in a significant protection against renal fibrosis (UUO). However, the strong BDL-induced damage that was observed in kidneys (expression of renal damage marker KIM-1 and the tubular damage score was elevated 4-fold) was not reduced in Yb-1+/- mice.

Conclusions: In summary, we demonstrate that YB-1 crucially contributes to hepatic and renal fibrosis, however not to the organ crosstalk between liver and kidney herein.

References cited:

[1] Hanssen et al. Y-box binding protein-1 mediates profibrotic effects of calcineurin inhibitors in the kidney. J Immunol. 2011;187:298 – 308.

[2] Hanssen et al. YB-1 is an early and central mediator of bacterial and sterile inflammation in vivo. J Immunol. 2013 191:2604 – 13.

[3] Raffetseder et al. Extracellular YB-1 blockade in experimental nephritis upregulates Notch-3 receptor expression and signaling. Nephron Exp Nephrol. 2011;118:e100 – 8.

Corresponding author: Weiskirchen, Ralf

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