In fact, serum BA levels in 8-week CBDL mice were 20-fold higher in WT mice (2,851 ± 1,097 μmol/L), compared to 8-week CBDL FXR−/− mice (110 ± 21 μmol/L), and kidney fibrosis in long-term

CBDL FXR−/− mice was indeed ameliorated, as demonstrated by Sirius Red staining and significantly lower renal hydroxyproline levels (Fig. 8B). To additionally rule out a general resistance of FXR−/− mice to renal fibrosis, we compared the degree of renal fibrosis in response to unilateral ureter ligation (UUL; as a noncholestatic condition). Selleckchem Epigenetics Compound Library Notably, we found no differences in fibrotic response after UUL in FXR−/− mice, compared to WT mice (Fig. 8C). Collectively, these findings indicate that FXR−/− mice are protected from long-term, but not early, CBDL-induced tubular epithelial injury, which can be explained by declining and less hydrophobic serum BA levels in FXR−/− mice (but not WT) over time. Next, we hypothesized AZD1208 chemical structure that prefeeding hydrophilic norUDCA 7 days before CBDL could protect against tubular epithelial injury,

because norUDCA represents the main BA in serum and urine after feeding and undergoes substantial renal elimination.[29] Indeed, norUDCA prefeeding was able to prevent tubular epithelial injury in 3-day CBDL mice, as demonstrated by PAS- and AQP2-stained kidney sections (Supporting Fig. 5). To substantiate our

concept with human pathological findings, we screened our pathological archives for patients with cholestatic liver disease and cholemic nephropathy in whom both tissues were available Quinapyramine for examination. Kidney histology frequently showed tubular casts, interstitial nephritis, and renal fibrosis as well as characteristic collecting duct lesions (Supporting Fig. 6). Renal tubular injury is a major, perhaps underestimated, and still poorly understood cause of renal dysfunction in advanced liver diseases.[3, 4, 30] We hypothesized that cholestatic liver dysfunction with systemic accumulation of potentially toxic BAs, together with their exaggerated compensatory urinary elimination, may contribute to AKI in such patients. Therefore, we established and characterized a mouse model of progressive cholestatic liver disease associated with tubulointerstitial nephritis and renal fibrosis and impaired renal function, which offers novel perspectives to study the mechanisms and novel treatment strategies for cholemic nephropathy.[9] Experimental studies from the 1940s and 1950s frequently used dogs and indeed showed structural renal alterations including interstitial nephritis and renal fibrosis in cholestasis.