The liver-kidney crosstalk: new mediators, mechanisms and kidney-protective options in hepatic fibrosis

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Primary damage to a central metabolic organ such as the liver often also causes systemic damage to secondarily affected organs such as the kidney. The underlying pathomechanisms of this organ crosstalk have so far been insufficiently investigated.As part of our own preliminary work, we have already demonstrated that the CXC chemokine-1 (CXCL1) and the protein Y-box protein (YB)-1 are involved in the process of liver/kidney crosstalk during hepatic fibrosis. Both proteins have a nonredundant role in hepatic, renal, and systemic inflammation, and initial pilot data suggest a repressive influence of YB-1 on Cxcl1 gene expression. In the model of bile duct ligation (BDL), semi-maximal YB-1 expression in Yb1+ / --mice had a protective effect on liver damage despite increased serum CXCL1 levels. The secondary affected kidneys of these animals were significantly stronger damaged. By organ-specific modulation of the YB-1 content (liver/kidney), we now want to test our hypothesis that YB-1 is a central factor of the organ crosstalk between liver and kidney and that its function in the kidney has protective character. In addition, further key proteins of the liver-kidney axis will be identified and the (YB-1-dependent) expression of CXC chemokines, their receptor CXCR2 and the signaling pathways involved will be investigated in detail. By applying a chemical component that specifically translocates YB-1 into the cell nucleus and thus mediates anti-fibrotic properties of the protein as well as through interventions in the CXCR2 signaling pathway, therapeutic approaches in liver fibrosis and liver-renal crosstalk are also examined.