Adaptive regulation of bile salt transporters in kidney and liver in obstructive cholestasis in the rat.
OBJECTIVE
Cholestasis results in adaptive regulation of bile salt transport proteins in hepatocytes that may limit liver injury. However, it is not known if changes also occur in the expression of bile salt transporters that reside in extrahepatic tissues, particularly the kidney, which might facilitate bile salt excretion during obstructive cholestasis.


METHODS
RNA and protein were isolated from liver and kidney 14 days after common bile duct ligation in rats and assessed by RNA protection assays, Western analysis, and tissue immunofluorescence. Sodium-dependent bile salt transport was also measured in brush border membrane vesicles from the kidney.


RESULTS
After common bile duct ligation, serum bile salts initially rose and then declined to lower levels after 3 days. In contrast, urinary bile salt excretion rose progressively over the 2-week period. By that time, the ileal sodium-dependent bile salt transporter messenger RNA and protein expression in total liver had increased to 300% and 200% of controls, respectively, while falling to 46% and 37% of controls, respectively, in the kidney. Sodium-dependent uptake of (3)H-taurocholate in renal brush border membrane vesicles was decreased. In contrast, the multidrug resistance-associated protein 2 expression in the kidney was increased 2-fold, even 1 day after ligation. Immunofluorescent studies confirmed the changes in the expression of these transporters in liver and kidney.


CONCLUSIONS
These studies show that the molecular expression of bile salt transporters in the kidney and cholangiocytes undergo adaptive regulation after common bile duct obstruction in the rat. These responses may facilitate extrahepatic pathways for bile salt excretion during cholestasis.
Lee
J
J
Liver Center and Department of Medicine, Yale University School of Medicine, 1080 LMP, New Haven, CT 06520-8019, USA.
Azzaroli
F
F
Wang
L
L
Soroka
C J
CJ
Gigliozzi
A
A
Setchell
K D
KD
Kramer
W
W
Boyer
J L
JL
D000222:Adaptation, Physiological; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002779:Cholestasis / Q000378:metabolism*; D003135:Common Bile Duct; D005455:Fluorescent Antibody Technique; D007668:Kidney / Q000378:metabolism*; D008026:Ligation; D008099:Liver / Q000378:metabolism*; D008297:Male; D008871:Microvilli / Q000378:metabolism; D024101:Mitochondrial Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012269:Ribosomal Proteins / Q000172:deficiency / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D027981:Symporters
D001647:Bile Acids and Salts; D002352:Carrier Proteins; C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D027981:Symporters; C071908:sodium-bile acid cotransporter