Mechanisms causing cholemic nephropathy

胆汁性肾病的发病机制

• 批准号: 528251440
• 负责人: Professor Dr. Jan G. Hengstler
• 金额: --
• 依托单位: Forschungsbereich Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/528251440?language=en
• 关键词: Mechanisms; causing; cholemic; nephropathy

Cholemic nephropathy (CN) is a severe, often fatal complication of several liver diseases and no specific treatment is currently available. In our previous work, we used bile duct ligation (BDL) in mice as a preclinical model of CN. We visualized bile flux in kidneys and livers using intravital imaging, supported by MALDI-MSI and LC-MS/MS. We showed that bile acids (BA) are reabsorbed from the renal tubular lumen into proximal renal tubular epithelial cells (TEC) and that BA enrichment in TEC is followed by cell death. At week 3 after BDL and later, damage of peritubular capillaries and massive leakage of BA into the renal interstitium were observed, followed by leukocyte infiltration and fibrosis. Since TEC express the apical sodium-dependent bile acid transporter (ASBT; Slc10a2), a BA uptake carrier, at their apical luminal membrane, we used the novel compound AS0369, a systemically bioavailable ASBT inhibitor, to block BA uptake. This almost completely prevented kidney injury up to 6 weeks after BDL, as evidenced by intravital imaging, kidney histology, transcriptomics, and urine and serum biomarkers. However, it remains currently unclear, if bile acids, bilirubin or other inflammatory mediators cause cholemic nephropathy. For the development of therapeutic strategies, it would be important to clarify the exact mechanism responsible for the disease. Therefore, the present project will clarify the following questions: What is the contribution of bile acids and bilirubin to cholemic nephropathy? In our previous work we have obtained evidence that bile acids may play a causal role, because AS0369 prevented cholemic nephropathy. However, AS0369 reduced both, systemic blood concentrations of bile acids and bilirubin. To establish a causal relationship, interventions to specifically modify either bile acids or bilirubin in TEC (the target cells of cholemic nephropathy) will be used. Does modification of hydrophilicity of bile acids modify cholemic nephropathy? It is well known that relatively hydrophilic bile acids are less toxic than hydrophobic bile acids also in kidney tissue. If bile acids are responsible for cell death events of TEC (and consequently for cholemic nephropathy), then interventions that lead to a more hydrophilic, ‘protective’ spectrum of bile acids should ameliorate the disease. If this is the case, the combination of both approaches – reducing bile acid reabsorption by ASBT inhibition and metabolic conditioning to generate a more hydrophilic bile acid spectrum – could lead to additive (or synergistic) therapeutic effects.

胆汁淤积性肾病（CN）是几种肝脏疾病的严重、常常致命的并发症，目前尚无专门的治疗方法。在我们之前的工作中，我们使用小鼠胆管结扎（BDL）作为CN的临床前模型。在MALDI-MSI和LC-MS/MS的支持下，我们使用活体成像来观察肾脏和肝脏的胆汁通量。我们发现胆汁酸（BA）从肾小管腔被重吸收到近端肾小管上皮细胞（TEC）中，并且BA在TEC中富集之后是细胞死亡。在BDL后第3周及以后，观察到肾小管周围毛细血管损伤，BA大量渗漏至肾间质，随后出现白细胞浸润和纤维化。由于TEC在其根尖管腔膜上表达钠依赖性胆汁酸转运体（ASBT; Slc10a2），这是一种BA摄取载体，因此我们使用了新的化合物AS0369，一种全身生物可利用的ASBT抑制剂，来阻止BA的摄取。活体成像、肾脏组织学、转录组学、尿液和血清生物标志物证明，这几乎完全防止了BDL后6周的肾损伤。然而，目前尚不清楚胆汁酸、胆红素或其他炎症介质是否会引起胆汁淤积性肾病。对于治疗策略的发展，弄清导致这种疾病的确切机制是很重要的。因此，本项目将澄清以下问题：胆汁酸和胆红素对胆汁淤积性肾病的贡献是什么？在我们之前的工作中，我们已经获得了胆汁酸可能起因果作用的证据，因为AS0369可以预防胆汁淤积性肾病。然而，AS0369降低了胆汁酸和胆红素的全身血液浓度。为了建立因果关系，将使用干预措施特异性地改变TEC（胆碱性肾病的靶细胞）中的胆汁酸或胆红素。胆汁酸亲水性的改变是否能改善胆汁淤积性肾病？众所周知，在肾组织中，相对亲水的胆汁酸比疏水的胆汁酸毒性更小。如果胆汁酸是TEC细胞死亡事件的原因（并因此导致胆碱性肾病），那么导致胆汁酸更亲水、“保护性”谱的干预措施应能改善疾病。如果是这样的话，两种方法的结合——通过ASBT抑制和代谢调节来减少胆汁酸的重吸收，从而产生更亲水的胆汁酸谱——可能会导致附加（或协同）的治疗效果。