Renal ASBT as a therapeutic target for cholemic nephropathy caused by cholestatic liver diseases
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Date
2025
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Abstract
Chronic liver diseases are prevalent, and a significant proportion of patients exhibit cholestasis, characterised by elevated bile acid concentrations in the general circulation. This exposure can result in adverse effects, including acute kidney injury, a frequently lethal complication of cholestatic liver disease. The potential role of bile acids in the pathogenesis of kidney injury has been a subject of speculation, leading to the term "cholemic nephropathy". However, the underlying mechanisms of this disease remain to be elucidated, and a specific therapeutic intervention remains elusive. To address this knowledge gap, a mouse model was employed, in which the common bile duct was ligated (BDL), resulting in elevated bile acid concentrations in the blood and various tissues. Subsequent to BDL, the mice were observed to develop kidney injury. The aim of my study was to illustrate the bile flux in renal tissue using intravital imaging. The study demonstrated that a fluorophore-coupled taurocholic acid (NBD-TCA) is taken up by proximal renal tubular epithelial cells (pTEC) and is enriched in this cell type. Following this enrichment, a series of observations were made, including cell death events of pTEC, immune cell infiltration, tubular dilatation and casts, leaky peritubular capillaries, fibrosis and enlarged glomeruli. These observations were subsequently confirmed through histological analysis and immune-staining of tissues, as well as analysis of biomarkers of kidney injury, including increased KIM-1, NGAL, cystatin C and, in the latest stages, creatinine. The subsequent study investigated the hypothesis that specific transporters may be responsible for the accumulation of bile acids in pTEC. Using specific inhibitors, I demonstrated that the inhibition of the apical sodium-dependent bile acid transporter (ASBT) almost completely blocked TCA accumulation in pTEC of mice after BDL. Importantly, ASBT inhibition prevented pTEC death events and strongly ameliorated all above described hallmarkers of kidney injury.
In conclusion, systemic ASBT inhibition may represent an efficient therapeutic strategy for the treatment of cholemic nephropathy if the results obtained in mice are relevant for the human situation.
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Cholemic nephropathy, Cholestatic liver diseeases, ASBT