Mechanisms causing cholemic nephropathy

• Applicant: Professor Dr. Jan G. Hengstler
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528251440

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.

• DFG Programme: Research Grants