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

Alvaro, Domenico; Onori, Paolo; Alpini, Gianfranco; Franchitto, Antonio; Jefferson, Douglas M.; Torrice, A.; Cardinale, Vincenzo; Stefanelli, Fabrizio; Mancino, Maria Grazia; Strazzabosco, Mario; Angélico, M.; Attili, Adolfo Francesco; Gaudio, Eugenio

doi:10.2353/ajpath.2008.070293

Cited by 76 publications

(89 citation statements)

References 51 publications

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“…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.…”

Section: Discussionmentioning

confidence: 89%

Food Restriction Ameliorates the Development of Polycystic Kidney Disease

Warner¹,

Hein²,

Nin³

et al. 2015

JASN

155

143

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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the accumulation of kidney cysts that ultimately leads to loss of renal function and kidney failure. At present, the treatment for ADPKD is largely supportive. Multiple studies have focused on pharmacologic approaches to slow the development of the cystic disease; however, little is known about the role of nutrition and dietary manipulation in PKD. Here, we show that food restriction (FR) effectively slows the course of the disease in mouse models of ADPKD. Mild to moderate (10%-40%) FR reduced cyst area, renal fibrosis, inflammation, and injury in a dose-dependent manner. Molecular and biochemical studies in these mice indicate that FR ameliorates ADPKD through a mechanism involving suppression of the mammalian target of the rapamycin pathway and activation of the liver kinase B1/AMP-activated protein kinase pathway. Our data suggest that dietary interventions such as FR, or treatment that mimics the effects of such interventions, may be potential and novel preventive and therapeutic options for patients with ADPKD.

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Section: Discussionmentioning

confidence: 89%

Food Restriction Ameliorates the Development of Polycystic Kidney Disease

Warner¹,

Hein²,

Nin³

et al. 2015

JASN

155

143

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“…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).…”

Section: Animals and Tissue Preparationmentioning

confidence: 99%

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

Šteffl

Schweiger

Mayer

et al. 2009

Histochem Cell Biol

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Previously it was shown that growth hormone (GH) and its receptor (GH-R) are involved in growth-promoting events during early embryonic development. However, it is still unknown if GH-induced GH-R signalling may support other functions within the oviduct. The purpose of our study was to analyse GH-R expression and localization in the porcine oviduct during different stages of the oestrus cycle and pregnancy (days 2-3 post inseminationem to days 65-71). As shown by reverse transcription polymerase chain reaction (RT-PCR), GH-R is expressed in the porcine oviduct during all stages of the oestrus cycle and pregnancy, respectively. Additionally, GH-R mRNA was detected in porcine conceptuses collected at day 18 of pregnancy. Using immunohistochemistry, GH-R was exclusively localized to the epithelium of the porcine oviduct throughout all segments examined. Localization of GH-R was mainly observed in the cytoplasm of ciliated epithelial cells. Generally, the number of GH-R-positive cells was elevated in the periovulatory phase of the oestrus cycle. Except for the isthmic epithelium, staining intensity of GH-R-positive cells was highest at oestrus and markedly reduced at met- and dioestrous stages. In infundibular and ampullar segments, percentage of GH-R-positive cells was significantly higher at days 2-3 post inseminationem compared to days 65-71 of pregnancy. Furthermore, in porcine conceptuses on day 18 of pregnancy GH-R protein expression was almost exclusively localized to trophectoderm. Our data suggest that GH-R mRNA and protein expression in the porcine oviduct throughout the oestrus cycle and pregnancy may suggest other activities of GH not described previously. Specifically, autocrine or paracrine GH-induced GH-R signalling may be linked to ciliated cell homeostasis of the porcine oviduct. Additionally, our results indicate that GH-R expression in the pig trophectoderm may be responsible for trophoblastic elongation.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Urribarri

Munoz‐Garrido

Perugorria

et al. 2014

Gut

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Objective Polycystic liver diseases (PCLDs) are genetic disorders characterised by progressive bile duct dilatation and/or cyst development. Their pathogenesis is a consequence of hyperproliferation, hypersecretion and microRNA alterations in cholangiocytes. Here we evaluate the role of matrix metalloproteases (MMPs) in the hepatic cystogenesis of PCLDs. Design Metalloprotease activity was measured by microfluorimetric assays in normal and polycystic cholangiocyte cultures from humans and rats, and gene expression by real time quantitative PCR. The role of cytokines, oestrogens and growth factors present in the cystic fluid of PCLD patients was evaluated for MMP activity. The MMP inhibitor marimastat was examined for cystic expansion in vitro and in polycystic kidney (PCK) rats. Results Polycystic human and rat cholangiocytes displayed increased MMP activity, which was associated with increased mRNA levels of different MMPs. Interleukin (IL)-6 and IL-8, and 17β-oestradiol, all stimulated MMP activity in human cholangiocytes. The presence of antibodies against IL-6 and/or IL-8 receptor/s inhibited baseline MMP hyperactivity of polycystic human cholangiocytes but had no effect on normal human cholangiocytes. MMP-3 was overexpressed in cystic cholangiocytes from PCLD human and PCK rat livers by immunohistochemistry. Marimastat reduced MMP hyperactivity of polycystic human and rat cholangiocytes and blocked the cystic expansion of PCK cholangiocytes cultured in three-dimensions. Chronic treatment of 8-week-old PCK rats with marimastat inhibited hepatic cystogenesis and fibrosis. Conclusions PCLDs are associated with cholangiocyte MMP hyperactivity resulting from autocrine/paracrine stimulation by IL-6 and IL-8. Inhibition of this MMP hyperactivity with marimastat decreased hepatic cystogenesis in vitro and in an animal model of PCLD, offering a potential therapeutic tool.

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

Cited by 76 publications

References 51 publications

Food Restriction Ameliorates the Development of Polycystic Kidney Disease

Food Restriction Ameliorates the Development of Polycystic Kidney Disease

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

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

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