Disease stage dependent efficacy of systemic apical sodium dependent bile acid transporter (ASBT) inhibition 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 systemic ASBT inhibitors (ASBTi) almost completely prevented CN. However, it is not clear if ASBTi could also be used for therapy or if they are only effective in prevention. Here, we studied the therapeutic effect of ASBTi in CN. ASBTi was administered twice daily for four weeks into bile duct-ligated mice (BDL) mice at four distinct CN stages: (I) an early stage with predominantly proximal tubular epithelial cell (TEC) death events (BDL day 3); (II) leaky peritubular capillaries and tubular dilatation stage (BDL week 3); (III) fibrosis stage (BDL week 6); and (IV) an advanced stage with glomerular cysts and reduced ASBT expression (BDL week 9). ASBTi caused massive urinary excretion and systemic reduction of bile acids at all disease stages. Recovery of the BDL-induced body weight loss and improvement of kidney damage biomarkers and survival were observed when ASBTi was applied up to stage III. RNA-sequencing revealed amelioration of BDL-induced gene expression changes by ASBTi at all stages with larger effect size at early stages. Histological analysis revealed significant reduction of replacement proliferation of TEC, cystic dilatation of renal tubules, capillary leakiness, and renal fibrosis when therapy was initiated up to stage III. Significant reduction of glomerular cysts was observed even when therapy started at stage IV. In conclusion, ASBTi showed a long therapeutic time-window in CN with stage-dependent effect size.

Publication History

Article published online:
20 January 2025