Gastrin reverses established cholangiocyte proliferation and enhanced secretin-stimulated ductal secretion of BDL rats by activation of apoptosis through increased expression of Ca2+- dependent PKC isoforms.
We posed these questions: (i) Does administration of gastrin to 1-week bile duct ligation (BDL) rats inhibits established cholangiocyte proliferation and ductal secretion? (ii) Is gastrin inhibition of cholangiocyte proliferation and secretion of BDL rats associated with enhanced apoptosis? (iii) Are gastrin's effects on cholangiocyte function associated with increased expression of protein kinase C (PKC) isoforms; and (iv) Is gastrin stimulation of cholangiocyte apoptosis regulated by the Ca2+-dependent PKC pathway?


METHODS
Seven days after BDL, rats were treated with gastrin by minipumps for 14 days. Cholangiocyte proliferation was assessed by measurement of the number of PCNA and CK-19 positive cholangiocytes in sections, and PCNA expression in cholangiocytes. Ductal secretion was determined by measurement of secretin-induced cAMP levels and choleresis. Apoptosis was evaluated by TUNEL analysis in sections and annexin-V staining in cholangiocytes. The expression of PKC isoforms was determined by immunoblots.


RESULTS
Gastrin inhibits established cholangiocyte proliferation and enhanced secretin-stimulated ductal secretion of BDL rats.Gastrin's effects on cholangiocyte function were associated with enhanced apoptosis and increased expression of PKC alpha, and beta I and II. Gastrin increases in cholangiocyte apoptosis were blocked by BAPTA/AM and H7.


CONCLUSIONS
Gastrin inhibits cholangiocyte proliferation and secretin-induced ductal secretion in BDL rats by increasing apoptosis through a PKC-mediated mechanism.
Glaser
Sharon
S
Division of Research and Education, Scott & White Hospital and The Texas A & M University System Health Science Center, College of Medicine, 76504, USA.
Alvaro
Domenico
D
Ueno
Yoshiyuki
Y
Francis
Heather
H
Marzioni
Marco
M
Phinizy
Jo Lynne
JL
Baumann
Brandy
B
Mancino
Maria Grazia
MG
Venter
Julie
J
LeSage
Gene
G
Alpini
Gianfranco
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D001652:Bile Ducts / Q000166:cytology*; D015415:Biomarkers / Q000032:analysis; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005755:Gastrins / Q000008:administration & dosage*; D007527:Isoenzymes / Q000096:biosynthesis / Q000187:drug effects; D008026:Ligation; D008297:Male; D023421:Models, Animal; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000096:biosynthesis* / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D012633:Secretin / Q000008:administration & dosage*; D013223:Statistics as Topic
D015415:Biomarkers; D005755:Gastrins; D007527:Isoenzymes; D018809:Proliferating Cell Nuclear Antigen; D012633:Secretin; D000242:Cyclic AMP; D011493:Protein Kinase C; D002118:Calcium