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

Abstract

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

Food Restriction Ameliorates the Development of Polycystic Kidney Disease

“…21,28 Although IGF-1 has been proposed to be secreted in cystic fluid of ADPKD patients and may increase proliferation of PKD1 cystic cells, there is little information on the role of IGF-1 in cystogenesis in ADPKD. 29,30 In our model, we observed that FR leads to suppression of circulating IGF-1 levels and expression of IGF-1 in the kidney (Supplemental Figure 9) It is possible that FR may prevent ADPKD via suppression of the IGF-1/IGF-1R pathway. However, the precise mechanistic role of IGF-1 in ADPKD and its implications for the effect of FR remain to be studied.…”

Expression and localization of growth hormone receptor in the oviduct of cyclic and pregnant pigs and mid-implantation conceptuses

“…Recently, this antibody was shown to be suitable for immunohistochemical experiments in paraYn-embedded tissues (Alvaro et al 2008). BrieXy, after deparaYnization endogenous peroxidase activity and nonspeciWc protein binding of the sections were blocked by 10% hydrogen peroxide solution in double-distilled water for 10 min at room temperature (RT) and 10% normal goat serum (Dako, Hamburg, Germany) for 30 min at RT, respectively, before incubation with the primary antibody at 4°C overnight in a humid chamber (Shandon, Frankfurt a.M., Germany).…”

Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases

“…However, for each patient, hepatic cysts grow steadily with age, both in number and size. Although both men and women can develop PCLDs, women usually present a stronger phenotype 1 2 4. Several cytokines, such as interleukin (IL)-6 and IL-8, oestrogens and growth factors (ie, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), epidermal growth factor (EGF), epithelial derived neutrophil activating peptide 78 (ENA78) and growth regulated oncogene α (GROα)) may be secreted by cholangiocytes lining the hepatic cysts and are present in high levels in cystic fluid 4–7.…”