Disease stage dependent efficacy of systemically inhibiting the apical sodiumdependent bile acid transporter in mice with cholemic nephropathy

Cholemic nephropathy (CN) is a severe complication of cholestasis-associated liver diseases with an unmet need for therapy. Recently, we identified the molecular mechanism of CN and showed that the systemic apical sodium-dependent bile acid transporter inhibitor (ASBTi) AS0369 prevented CN in mice. However, it is not clear if ASBTi can be useful in a therapeutic setting. In the present study, we investigated the therapeutic time-window of ASBTi in mice with CN. AS0369 was administered twice daily at 60 mg/kg for four weeks to bile duct-ligated (BDL) mice at four CN stages: (1) early stage with proximal tubular epithelial cell (pTEC) death events (BDL day 3); (2) inflammation, leaky peritubular capillaries, and tubular dilatation (BDL day 21); (3) fibrosis (BDL day 42); and (4) advanced stage with glomerular cysts (BDL day 63). Disease progression was evaluated by biochemical, histopathological, immunohistochemical, MALDI-MSI, and RNA-sequencing analysis. RNA-sequencing revealed reduced BDL-induced gene deregulation by ASBTi at all stages with a larger effect size at early stages.