Inhibition of the Renal Apical Sodium-Dependent Bile Acid Transporter Prevents Cholemic Nephropathy in Bile Duct ligated Mice

Cholemic nephropathy (CN) is a severe complication of cholestasis-associated liver diseases, and no specific treatment is available. To understand the driving mechanism and identify therapeutic strategies, obstructive cholestasis was induced by bile duct ligation (BDL) in mice; bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI-MSI and LC-MS/MS. We show that proximal tubular epithelial cells (TEC) reabsorbed and enriched BA after BDL, leading to oxidative stress and death of proximal TEC, casts in distal tubules and collecting ducts, damage and leakiness of peritubular capillaries, and glomerular cysts. Since TEC express the apical sodium-dependent bile acid transporter (ASBT) at their luminal membrane, we used the novel compound AS0369, a systemically bioavailable ASBT inhibitor, to block BA uptake. Inhibition of the renal ASBT almost completely prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA spectrum. To check the translational relevance, we analyzed serum BA, bilirubin, and kidney injury molecule (KIM-1) in patients with advanced liver disease. In a multiple linear regression model, only sum BA was kept as explanatory variable for KIM-1, while bilirubin was excluded. Furthermore, analysis of ASBT expression in kidney biopsies from CN patients showed preserved expression which further highlights the translational relevance of the finding in mice. In conclusion, BA enrichment in TEC is an early key event in CN pathogenesis. Inhibiting renal ASBT and consequently BA uptake into TEC prevents CN and systemically decreases BA concentrations.

 

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Publication History

Article published online:
23 January 2024