VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/−) mice

2007 ◽  
Vol 293 (1) ◽  
pp. C419-C428 ◽  
Author(s):  
Claudia R. Amura ◽  
Kelley S. Brodsky ◽  
Rachel Groff ◽  
Vincent H. Gattone ◽  
Norbert F. Voelkel ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Liver Cyst ◽  
Cyst Fluid ◽  
Vegf Receptor ◽  
In Vitro Proliferation ◽  
Vegf Signaling ◽  
Cyst Growth ◽  
Cyst Fluids

Proliferation of cyst-lining epithelial cells is an integral part of autosomal dominant polycystic kidney disease (ADPKD) cyst growth. Cytokines and growth factors within cyst fluids are positioned to induce cyst growth. Vascular endothelial growth factor (VEGF) is a pleiotropic growth factor present in ADPKD liver cyst fluids (human 1,128 ± 78, mouse 2,787 ± 136 pg/ml) and, to a lesser extent, in ADPKD renal cyst fluids (human 294 ± 41, mouse 191 ± 90 pg/ml). Western blotting showed that receptors for VEGF (VEGFR1 and VEGFR2) were present in both normal mouse bile ducts and pkd2(WS25/−) liver cyst epithelial cells. Treatment of pkd2(WS25/−) liver cyst epithelial cells with VEGF (50–50,000 pg/ml) or liver cyst fluid induced a proliferative response. The effect on proliferation of liver cyst fluid was inhibited by SU-5416, a potent VEGF receptor inhibitor. Treatment of pkd2(WS25/−) mice between 4 and 8 mo of age with SU-5416 markedly reduced the cyst volume density of the liver (vehicle 9.9 ± 4.3%, SU-5416 1.8 ± 0.7% of liver). SU-5416 treatment between 4 and 12 mo of age markedly protected against increases in liver weight [pkd2(+/+) 4.8 ± 0.2%, pkd2(WS25/−)-vehicle 10.8 ± 1.9%, pkd2(WS25/−)-SU-5416 4.8 ± 0.4% body wt]. The capacity of VEGF signaling to induce in vitro proliferation of pkd2(WS25/−) liver cyst epithelial cells and inhibition of in vivo VEGF signaling to retard liver cyst growth in pkd2(WS25/−) mice indicates that the VEGF signaling pathway is a potentially important therapeutic target in the treatment of ADPKD liver cyst disease.

scholarly journals CXCR2 agonists in ADPKD liver cyst fluids promote cell proliferation

2008 ◽  
Vol 294 (3) ◽  
pp. C786-C796 ◽  
Author(s):  
Claudia R. Amura ◽  
Kelley S. Brodsky ◽  
Berenice Gitomer ◽  
Kim McFann ◽  
Gwendal Lazennec ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cells ◽  
Cell Model ◽  
Intrahepatic Bile Duct ◽  
Mechanical Stretch ◽  
Liver Cyst ◽  
Microvascular Endothelial Cell ◽  
Promote Cell Proliferation ◽  
Cyst Growth ◽  
Cyst Fluids

Autosomal dominant polycystic kidney disease (ADPKD) is a highly prevalent genetic disease that results in cyst formation in kidney and liver. Cytokines and growth factors secreted by the cyst-lining epithelia are positioned to initiate autocrine/paracrine signaling and promote cyst growth. Comparative analyses of human kidney and liver cyst fluids revealed disparate cytokine/growth factor profiles. CXCR2 agonists, including IL-8, epithelial neutrophil-activating peptide (ENA-78), growth-related oncogene-α (GRO-α), are potent proliferative agents that were found at high levels in liver but not kidney cyst fluids. Liver cysts are lined by epithelial cells derived from the intrahepatic bile duct (i.e., cholangiocytes). In polarized pkd2(WS25/−) mouse liver cyst epithelial monolayers, CXCR2 agonists were released both apically and basally, indicating that they may act both on the endothelial and epithelial cells within or lining the cyst wall. IL-8 and human liver cyst fluid induced cell proliferation of HMEC-1 cells, a human microvascular endothelial cell line, and Mz-ChA1 cells, a human cholangiocyte cell model. IL-8 expression can be regulated by specific stresses. Hypoxia and mechanical stretch, two likely stressors acting on the liver cyst epithelia, significantly increased IL-8 secretion and promoter activity. AP-1, c/EBP, and NF-κB were required but not sufficient to drive the stress-induced increase in IL-8 transcription. An upstream element between −272 and −1,481 bp allowed for the stress-induced increase in IL-8 transcription. These studies support the hypothesis that CXCR2 signaling promotes ADPKD liver cyst growth.

scholarly journals Sorafenib inhibits cAMP-dependent ERK activation, cell proliferation, and in vitro cyst growth of human ADPKD cyst epithelial cells

2010 ◽  
Vol 299 (5) ◽  
pp. F944-F951 ◽  
Author(s):  
Tamio Yamaguchi ◽  
Gail A. Reif ◽  
James P. Calvet ◽  
Darren P. Wallace
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Small Molecule ◽  
Therapeutic Option ◽  
Three Dimensional ◽  
Collagen Gel ◽  
Erk Signaling ◽  
Cyst Growth

In autosomal dominant polycystic kidney disease (ADPKD), aberrant proliferation of the renal epithelial cells is responsible for the formation of numerable fluid-filled cysts, massively enlarged kidneys, and progressive loss of renal function. cAMP agonists, including arginine vasopressin, accelerate cyst epithelial cell proliferation through protein kinase A activation of the B-Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway. The mitogenic effect of cAMP is equally potent and additive to growth factor stimulation. Here, we determined whether Sorafenib (BAY 43–9006), a small molecule Raf inhibitor, inhibits proliferation of cells derived from the cysts of human ADPKD kidneys. We found that nanomolar concentrations of Sorafenib reduced the basal activity of ERK, inhibited cAMP-dependent activation of B-Raf and MEK/ERK signaling, and caused a concentration-dependent inhibition of cell proliferation induced by cAMP, epidermal growth factor, or the combination of the two agonists. Sorafenib completely blocked in vitro cyst growth of human ADPKD cystic cells cultured within a three-dimensional collagen gel. These data demonstrate that cAMP-dependent proliferation of human ADPKD cyst epithelial cells is blocked by Sorafenib and suggest that small molecule B-Raf inhibitors may be a therapeutic option to reduce the mitogenic effects of cAMP on cyst expansion.

scholarly journals ATP Release Mechanisms in Primary Cultures of Epithelia Derived from the Cysts of Polycystic Kidneys

1999 ◽  
Vol 10 (2) ◽  
pp. 218-229
Author(s):  
PATRICIA D. WILSON ◽  
JEFFREY S. HOVATER ◽  
CASH C. CASEY ◽  
JAMES A. FORTENBERRY ◽  
ERIK M. SCHWIEBERT
Keyword(s):  
Epithelial Cells ◽  
Primary Cultures ◽  
Atp Release ◽  
Cyst Fluid ◽  
Extracellular Nucleotides ◽  
Channel Blockers ◽  
Ion Channel Blockers ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Fluids

Abstract. Autosomal dominant polycystic kidney disease (ADPKD) cyst enlargement is exacerbated by accumulation of fluid within the lumen of the cyst. Extracellular nucleotides and nucleosides stimulate fluid and chloride (Cl-) secretion across epithelia and are potent autocrine and paracrine agonists within tissues. This study tests the hypothesis that ATP may be released by ADPKD epithelial cells. Once released, extracellular nucleotides and their metabolites may become “trapped” in the cyst lumen. As a consequence, extracellular ATP may augment ADPKD cyst enlargement through stimulation of salt and water secretion across ADPKD epithelia that encapsulate ADPKD cysts. To test this hypothesis, bioluminescence detection assays of ATP released from primary cultures of human ADPKD epithelial cells were compared with non-ADPKD human epithelial primary cultures. ADPKD cultures release comparable or greater amounts of ATP than non-ADPKD cultures derived from proximal tubule or cortex. ATP release in both ADPKD and non-ADPKD primary epithelial monolayers was directed largely into the apical medium; however, basolateral-directed ATP release under basal and stimulated conditions was also observed. Hypotonicity potentiated ATP release into the apical and basolateral medium in a reversible manner. Reconstitution of isotonic conditions with specific osmoles or inhibition with mechanosensitive ion channel blockers dampened hypotonicity-induced ATP release. “Flashfrozen” cyst fluids from ADPKD cysts, harvested from multiple donor kidneys, were screened by luminometry. A subset of cyst fluids contained as much as 0.5 to 10 μM ATP, doses sufficient to stimulate purinergic receptors. Taken together, these results show that ADPKD and non-ADPKD human epithelial primary cultures release ATP under basal and stimulated conditions and that ATP is released in vitro and into the cyst fluid by cystic epithelial cells in concentrations sufficient to stimulate ATP receptors. It is hypothesized that extracellular nucleotide release and signaling may contribute detrimentally to the gradual expansion of cyst fluid volume that is a hallmark of ADPKD.

scholarly journals Growth factor induced proliferation, migration, and lumen formation of rat endometrial epithelial cells in vitro

2016 ◽  
Vol 62 (3) ◽  
pp. 271-278 ◽  
Author(s):  
Md. Rashedul ISLAM ◽  
Kazuki YAMAGAMI ◽  
Yuka YOSHII ◽  
Nobuhiko YAMAUCHI
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Lumen Formation ◽  
Endometrial Epithelial Cells

Transforming growth factor-β3 protection of epithelial cells from cycle-selective chemotherapy in vitro

1997 ◽  
Vol 53 (8) ◽  
pp. 1149-1159 ◽  
Author(s):  
E.Siobhan McCormack ◽  
Gary V. Borzillo ◽  
Claire Ambrosino ◽  
Gilda Mak ◽  
Laurie Hamablet ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Selective Chemotherapy

scholarly journals Cyst fluid from human autosomal dominant polycystic kidneys promotes cyst formation and expansion by renal epithelial cells in vitro.

1992 ◽  
Vol 3 (4) ◽  
pp. 984-994
Author(s):  
M Ye ◽  
M Grant ◽  
M Sharma ◽  
L Elzinga ◽  
S Swan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Autosomal Dominant ◽  
Renal Cysts ◽  
Secretory Activity ◽  
Collagen Matrix ◽  
Fluid Secretion ◽  
Cyst Formation ◽  
Cyst Fluid ◽  
Epidermal Growth

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive renal enlargement, culminating in renal insufficiency in over one half of affected individuals. The highly variable onset and clinical course of ADPKD may be due to factors extrinsic to the genetically defined renal cysts. In this study, cyst fluid samples from 12 nonazotemic and 18 azotemic ADPKD subjects were examined for in vitro biologic activity that promotes cellular proliferation and the secretion of fluid by renal epithelial monolayers, two pathogenetic mechanisms that have critical roles in the formation and the rate of expansion of renal cysts. Cyst fluid added to culture medium (final concentrations, 1 to 20%) caused Madin-Darby canine kidney cells and human kidney cortex (HKC) cells derived from primary cultures to form cysts in Type I collagen matrix. Cyst fluid stimulated the net transepithelial secretion of fluid by polarized monolayers composed of these same cells. Absolute levels of fluid secretory activity determined by MDCK bioassay were correlated directly with the rate of fluid secretion by HKC cell monolayers and with the extent of cyst formation by MDCK and HKC cells embedded in collagen matrix. The secretory activity of urine was negligible; secretory activity was detectable in the serum of normal and ADPKD subjects, but the levels were much lower than in cyst fluid. cAMP agonists prostaglandins E1 and E2, arginine vasopressin, and 8-Br-cAMP stimulated fluid secretion by MDCK and HKC monolayers, but these substances did not cause HKC cells to form cysts in collagen matrix, whereas cyst fluid did. Among other naturally occurring growth factors and autacoids, only epidermal growth factor and transforming growth factor alpha stimulated cyst formation by HKC cells; however, the capacity of cyst fluid to stimulate fluid secretion was not affected by treatment with antiserum to epidermal growth factor. It was concluded that potent, and possibly unique, substances in the cyst fluids of individuals with ADPKD support and augment biologic processes in renal epithelial cells that may be important in the promotion of progressive cyst expansion.

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