Morphological and functional features of hepatic cyst epithelium in autosomal dominant polycystic kidney disease.
We evaluated the morphological and functional features of hepatic cyst epithelium in adult autosomal dominant polycystic kidney disease (ADPKD). In six ADPKD patients, we investigated the morphology of cyst epithelium apical surface by scanning electron microscopy and the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF1), IGF1 receptors (IGF1-R), growth hormone receptor, the proliferation marker proliferating cell nuclear antigen, and pAKT by immunohistochemistry and immunofluorescence. Proliferation of liver cyst-derived epithelial cells was evaluated by both MTS proliferation assay and [(3)H]thymidine incorporation into DNA. The hepatic cyst epithelium displayed heterogeneous features, being normal in small cysts (<1 cm), characterized by rare or shortened cilia in 1- to 3-cm cysts, and exhibiting the absence of both primary cilia and microvilli in large cysts (>3 cm). Cyst epithelium showed marked immunohistochemical expression of ER, growth hormone receptor, IGF1, IGF1-R, proliferating cell nuclear antigen, and pAKT. IGF1 was 10-fold more enriched in the hepatic cyst fluid than in serum. Serum-deprived liver cyst-derived epithelial cells proliferated when exposed to 17beta-estradiol and IGF1 and when exposed to human cyst fluid. ER or IGF1-R antagonists inhibited the proliferative effect of serum readmission, cyst fluid, 17beta-estradiol, and IGF1. Our findings could explain the role of estrogens in accelerating the progression of ADPKD and may suggest a potential benefit of therapeutic strategies based on estrogen antagonism.
Alvaro
Domenico
D
Department of Clinical Medicine, University of Rome Sapienza, via R. Rossellini 51, 00137 Rome, Italy. domenico.alvaro@uniroma1
Onori
Paolo
P
Alpini
Gianfranco
G
Franchitto
Antonio
A
Jefferson
Douglas M
DM
Torrice
Alessia
A
Cardinale
Vincenzo
V
Stefanelli
Fabrizio
F
Mancino
Maria Grazia
MG
Strazzabosco
Mario
M
Angelico
Mario
M
Attili
Adolfo
A
Gaudio
Eugenio
E
D000368:Aged; D015153:Blotting, Western; D049109:Cell Proliferation; D002923:Cilia / Q000648:ultrastructure; D020420:Cyst Fluid / Q000378:metabolism; D003560:Cysts / Q000209:etiology / Q000648:ultrastructure*; D004848:Epithelium / Q000378:metabolism / Q000648:ultrastructure*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000494:pharmacology; D008107:Liver Diseases / Q000209:etiology / Q000473:pathology*; D008297:Male; D008855:Microscopy, Electron, Scanning; D008875:Middle Aged; D007690:Polycystic Kidney Diseases / Q000150:complications* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors
D011960:Receptors, Estrogen; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1