Inhibition of the Renal Apical Sodium Dependent Bile Acid Transporter Prevents Cholemic Nephropathy in Mice with Obstructive Cholestasis.

Ghallab, Ahmed; González, Daniela; Strängberg, Ellen; Hofmann, Ute; Myllys, Maiju; Hassan, Reham; Hobloss, Zaynab; Brackhagen, Lisa; Begher-Tibbe, Brigitte; Duda, Julia C; Drenda, Carolin; Kappenberg, Franziska; Reinders, Joerg; Friebel, Adrian; Vucur, Mihael; Turajski, Monika; Seddek, Abdel-Latief; Abbas, Tahany; Abdelmageed, Noha; Morad, Samy A F; ... (2024). Inhibition of the Renal Apical Sodium Dependent Bile Acid Transporter Prevents Cholemic Nephropathy in Mice with Obstructive Cholestasis. Journal of hepatology, 80(2), pp. 268-281. Elsevier 10.1016/j.jhep.2023.10.035

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BACKGROUND & AIMS

Cholemic nephropathy (CN) is a severe complication of cholestasis-associated liver diseases, with no specific treatment. We revisited the pathophysiology to identify therapeutic strategies.

METHODS

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. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed by ASBT immunostaining in kidney biopsies of CN patients, analysis of mice with humanized BA spectrum, and by analysis of serum bile acids (BA) and kidney injury molecule (KIM-1) in liver disease and hyperbilirubinemia patients.

RESULTS

Proximal tubular epithelial cells (TEC) reabsorbed and enriched BA, leading to oxidative stress and death of proximal TEC, casts in distal tubules and collecting ducts, peritubular capillaries leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TEC and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In advanced liver disease patients, serum BA were the main determinant of KIM-1 levels. ASBT expression in TEC was preserved in biopsies from CN patients, further highlighting the translational potential of targeting ASBT for treatment of CN.

CONCLUSIONS

BA enrichment in proximal TEC followed by oxidative stress and cell death is an early key event in CN. Inhibiting renal ASBT and consequently BA enrichment in TEC prevents CN and systemically decreases BA concentrations.

IMPACT AND IMPLICATIONS

Cholemic nephropathy (CN) is a severe complication of cholestasis with an unmet clinical need for therapy. We demonstrate that CN is triggered by the renal accumulation of bile acids (BA)- that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells (TEC) of the kidney take up BA via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in TEC, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for CN patients.

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