Abstract: TH-PO326

Onset and Resolution of Renal Inflammation Is Orchestrated by YB-1

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Ostendorf, Tammo, RWTH University Aachen, Nephrology, 52074 Aachen, Germany
  • Djudjaj, Sonja, University Hospital RWTH Aachen, Aachen, Germany
  • Breitkopf, Daniel Maximilian, University Hospital RWTH Aachen, Aachen, Germany
  • Rauen, Thomas, University Hospital Aachen, Aachen, Germany
  • Hermert, Daniela, Uniklinik Aachen, Aachen, Germany
  • Martin, Ina V., RWTH University of Aachen, Aachen, Germany
  • Boor, Peter, RWTH University Aachen, Aachen, Germany
  • Floege, Jürgen, RWTH University of Aachen, Aachen, Germany
  • Raffetseder, Ute, Div. of Nephrology, University Hospital Aachen, Aachen, Germany
Background

The Y-box-binding protein (YB)-1 plays a non-redundant role in both, systemic and local inflammatory responses. During the onset of inflammation, YB-1 upregulates the expression of pro-inflammatory factors such as interleukin (IL)-6 and CCL5. However, anti-inflammatory properties of YB-1 via a trans-repressive capacity on the Ccl5 promoter upon macrophage differentiation have also been described. Thus, YB-1 influences the early phase of inflammation and also seems to contribute to its termination in the later phase.

Methods

We analyzed YB-1-mediated expression of the anti-inflammatory cytokine IL-10 in cell culture assays and in vivo in both, LPS induced inflammation and sterile inflammation induced by unilateral renal ischemia-reperfusion (I/R) in mice with half-maximal expression of YB-1 (Yb1+/- mice) and their wild type (WT) littermates. Parameters of renal inflammation/fibrosis were determined by immunohistochemistry and qRT-PCR. Il10 gene regulation was investigated by ex vivo chromatin immunoprecipitation in kidney tissues.

Results

Within a decisive cis-regulatory region of the IL10 gene locus, the 4th intron, we identified and characterized an operative YB-1 binding site via gel shift experiments and reporter assays in immune and different renal cells. In vivo, YB-1 phosphorylated at serine 102 localized to the 4th intron, which was paralleled by enhanced Il10 mRNA expression in mice following LPS challenge and in I/R. Yb1+/- mice had diminished IL-10 expression upon LPS challenge. In I/R, Yb1+/- mice exhibited reduced kidney injury/inflammation in the early phase (days 1 and 5), however they exhibited aggravated long-term damage (day 21) with increased expression of Il10 together with known mediators of renal injury and inflammation compared to their WT littermates.

Conclusion

In conclusion, these data support the notion that there are context-specific decisions concerning YB-1 function and that a fine-tuning of YB-1 e.g. via a post-translational modification regulates its activity and/or localization that is crucial for systemic processes such as inflammation.