Published online before print January 17, 2008

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(American Journal of Pathology. 2008;172:321-332.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070293

Morphological and Functional Features of Hepatic Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease

Domenico Alvaro^*, Paolo Onori, Gianfranco Alpini^¶, Antonio Franchitto, Douglas M. Jefferson^||, Alessia Torrice^*, Vincenzo Cardinale^*, Fabrizio Stefanelli^*, Maria Grazia Mancino^*, Mario Strazzabosco^**, Mario Angelico, Adolfo Attili^* and Eugenio Gaudio

From the Division of Gastroenterology^*and the Department of Anatomy,University of Rome, "Sapienza," Rome, Italy; CeLiveR,^**Division of Gastroenterology, Ospedali Riuniti di Bergamo, Bergamo, Italy and Digestive Diseases Section,Yale University, New Haven, Connecticut; the University of Rome "Sapienza,"Polo Pontino, Latina, Italy; Gastroenterology Unit,Department of Public Health, University of Rome Tor Vergata, Rome, Italy; the Department of Experimental Medicine,University of L’Aquila, L’Aquila, Italy; the Department of Internal Medicine and Medical Physiology,^¶Scott and White Hospital and Texas A&M University System Health Science Center, College of Medicine, and Central Texas Veterans Health Care System, Temple, Texas; and the Department of Physiology,||Tufts University School of Medicine, Boston, Massachusetts

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 [³H]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 17β-estradiol and IGF1 and when exposed to human cyst fluid. ER or IGF1-R antagonists inhibited the proliferative effect of serum readmission, cyst fluid, 17β-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.

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