Inhibition of the Renal Apical Sodium Dependent Bile Acid Transporter Prevents Cholemic Nephropathy
Cholemic nephropathy (CN) is a severe complication of cholestasis-associated liver diseases, and no specific treatment is available. To understand the underlying pathomechanism, we induced cholestasis in mice by bile duct ligation and visualized bile flux in kidneys and livers using intravital imaging. We show 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, damage of peritubular capillaries and fibrosis. Since TEC express the apical sodium-dependent bile acid transporter (ASBT) at their apical luminal membrane, we used AS0369, a systemically bioavailable ASBT inhibitor, to block BA uptake. This almost completely prevented kidney injury as evidenced by intravital imaging, kidney histology, transcriptomics, and urine as well as serum biomarkers. Preserved ASBT expression in human TEC was demonstrated in biopsies from CN patients, highlighting the translational potential of treating CN by targeting ASBT. The present data set includes an RNA-seq analysis that was performed for three groups of mice: (1) sham operated controls; (2) mice with common bile duct ligation and vehicle treatment; (3) mice with common bile duct ligation and therapy with the ASBT inhibitor AS0369.