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

对中枢代谢器官（如肝脏）的原发损害通常也会对继发受影响的器官（如肾脏）造成全身性损害。到目前为止，这种器官串扰的潜在病理机制尚未得到充分的研究。作为我们自己前期工作的一部分，我们已经证明了CXC趋化因子-1 （CXCL1）和蛋白Y-box蛋白(YB)-1参与肝纤维化期间的肝/肾串扰过程。这两种蛋白在肝脏、肾脏和全身炎症中都有非冗余的作用，初步试验数据表明YB-1对Cxcl1基因表达有抑制作用。在胆管结扎（BDL）模型中，尽管血清CXCL1水平升高，Yb1+ / -小鼠的半最大YB-1表达对肝损伤具有保护作用。继发性病变肾脏损伤明显较强。通过对YB-1含量（肝/肾）的器官特异性调节，我们现在想要验证我们的假设，即YB-1是肝脏和肾脏之间器官串扰的中心因素，其在肾脏中的功能具有保护作用。此外，将进一步鉴定肝肾轴的关键蛋白，并详细研究CXC趋化因子（yb -1依赖性）及其受体CXCR2的表达及其所涉及的信号通路。通过应用一种化学成分特异性地将YB-1易位到细胞核中，从而介导该蛋白的抗纤维化特性，以及通过干预CXCR2信号通路，研究了肝纤维化和肝肾串扰的治疗方法。

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.