NorUrsodeoxycholic acid ameliorates cholemic nephropathy in bile duct ligated mice
Krones E, Eller K, Pollheimer MJ, Racedo S, Kirsch AH, Frauscher B, Wahlström A, Ståhlman M, Trauner M, Grahammer F, Huber TB, Wagner K, Rosenkranz AR, Marschall HU, Fickert P.
BACKGROUND & AIMS:
Severe cholestasis may cause cholemic nephropathy that can be modeled in common bile duct ligated (CBDL) mice. We aimed to explore the therapeutic efficacy and mechanisms of norursodeoxycholic acid (norUDCA) in cholemic nephropathy.
METHODS:
In 8-weeks CBDL mice fed norUDCA (prior or post CBDL) or chow we evaluated serum urea levels, urine cytology and urinary neutrophil gelatinase associated lipocalin (uNGAL), kidney and liver tissue including quantification of fibrosis by hydroxyproline content and gene chip expression including key genes of inflammation and fibrosis. Moreover, we comprehensively analyzed bile acid profiles in liver, kidney, serum and urine.
RESULTS:
NorUDCA-fed CBDL mice had significantly lower serum urea and uNGAL levels and less severe cholemic nephropathy as demonstrated by normal urine cytology, significantly reduced tubulointerstitial nephritis, and renal fibrosis as compared to controls. NorUDCA underwent extensive metabolism towards even more hydrophilic compounds that were significantly enriched in kidneys.
CONCLUSION:
NorUDCA ameliorates cholemic nephropathy due to the formation of highly hydrophilic metabolites enriched in kidney. Consequently, norUDCA may represent a medical treatment for cholemic nephropathy.
LAY SUMMARY:
The term cholemic nephropathy describes renal dysfunction together with characteristic morphological alterations of the kidney in obstructive cholestasis that can be mimicked by ligation of the common bile duct in mice. Feeding the hydrophilic bile acid norUDCA to bile duct ligated mice leeds to significant amelioration of the renal phenotype due to the formation of highly hydrophilic metabolites enriched in kidney and may therefore represent a medical treatment for cholemic nephropathy.
