Effects of Thrombin on RPE Cells Are Mediated by Transactivation of Growth Factor Receptors

Hollborn, Margrit; Petto, Carola; Steffen, Anȷa; Trettner, Susanne; Bendig, Andrea; Wiedemann, Peter; Bringmann, Andreas; Kohen, Leon

doi:10.1167/iovs.08-3194

Cited by 29 publications

(19 citation statements)

References 42 publications

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“…However, treatment of the cultures with curcumin for 6 h resulted in a significant ( P <0.05) decrease in the gene expression of VEGF compared to control. The secretion of VEGF protein from RPE cells was previously described to be stimulated by PDGF and under chemical hypoxia conditions induced by addition of CoCl 2 to the culture medium [48], [49]. Curcumin had a dose-dependent inhibitory effect on the secretion of VEGF from RPE cells.…”

Section: Resultsmentioning

confidence: 77%

Cytotoxic Effects of Curcumin in Human Retinal Pigment Epithelial Cells

et al. 2013

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BackroundCurcumin from turmeric is an ingredient in curry powders. Due to its antiinflammatory, antioxidant and anticarcinogenic effects, curcumin is a promising drug for the treatment of cancer and retinal diseases. We investigated whether curcumin alters the viability and physiological properties of human retinal pigment epithelial (RPE) cells in vitro.Methodology/Principal FindingsCellular proliferation was investigated with a bromodeoxy-uridine immunoassay, and chemotaxis was investigated with a Boyden chamber assay. Cell viability was determined by trypan blue exclusion. Apoptosis and necrosis rates were determined with a DNA fragmentation ELISA. Gene expression was determined by real-time PCR, and secretion of VEGF and bFGF was examined with ELISA. The phosphorylation level of proteins was revealed by Western blotting. The proliferation of RPE cells was slightly increased by curcumin at 10 µM and strongly reduced by curcumin above 50 µM. Curcumin at 50 µM increased slightly the chemotaxis of the cells. Curcumin reduced the expression and secretion of VEGF under control conditions and abolished the VEGF secretion induced by PDGF and chemical hypoxia. Whereas low concentrations of curcumin stimulated the expression of bFGF and HGF, high concentrations caused downregulation of both factors. Curcumin decreased dose-dependently the viability of RPE cells via induction of early necrosis (above 10 µM) and delayed apoptosis (above 1 µM). The cytotoxic effect of curcumin involved activation of caspase-3 and calpain, intracellular calcium signaling, mitochondrial permeability, oxidative stress, increased phosphorylation of p38 MAPK and decreased phosphorylation of Akt protein.ConclusionIt is concluded that curcumin at concentrations described to be effective in the treatment of tumor cells and in inhibiting death of retinal neurons (∼10 µM) has adverse effects on RPE cells. It is suggested that, during the intake of curcumin as concomitant therapy of cancer or in the treatment of eye diseases, retinal function should be monitored carefully.

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Section: Resultsmentioning

confidence: 77%

Cytotoxic Effects of Curcumin in Human Retinal Pigment Epithelial Cells

et al. 2013

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“…Several pathogenic mechanisms contribute to visual function deterioration through hemorrhage: iron toxicity, oxidative damage from hemoglobin and its derivate, impairment of the blood-retinal barrier, and direct damage to the photoreceptor segment through the effect of mechanical forces are all related to the presence and persistence of retinal hemorrhages. [25][26][27] Upregulation of angiogenic factors via the coagulation cascade may represent an additional important mechanism by which the hemorrhagic component might contribute to the persistence of macular edema and the progression of CNV. 21,22 In addition to these well-known factors, new elements have emerged from the study of cellular responses in the presence of activated coagulation factors.…”

Section: Discussionmentioning

confidence: 99%

Intravitreal Ranibizumab for Choroidal Neovascularization With Large Submacular Hemorrhage in Age-Related Macular Degeneration

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Introini

et al. 2014

Retina

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“…These findings has led to the suggestion that the simultaneous inhibition of various angiogenic factors will have greater therapeutic benefit regarding antiangiogenesis in wet AMD than inhibition of VEGF-A alone [10]. In addition to VEGF-A, RPE cells produce further members of the human VEGF family, i.e., VEGF-B, -C, and -D, as well as placental growth factor (PlGF) [11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Osmotic induction of placental growth factor in retinal pigment epithelial cells in vitro: contribution of NFAT5 activity

et al. 2016

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One risk factor of neovascular age-related macular degeneration is systemic hypertension; hypertension is mainly caused by extracellular hyperosmolarity after consumption of dietary salt. In retinal pigment epithelial (RPE) cells, high extracellular osmolarity induces vascular endothelial growth factor (VEGF)-A (Hollborn et al. in Mol Vis 21:360-377, 2015). The aim of the present study was to determine whether extracellular hyperosmolarity and chemical hypoxia trigger the expression of further VEGF family members including placental growth factor (PlGF) in human RPE cells. Hyperosmotic media were made up by addition of 100 mM NaCl or sucrose. Chemical hypoxia was induced by CoCl2. Gene expression was quantified by real-time RT-PCR, and secretion of PlGF-2 was investigated with ELISA. Nuclear factor of activated T cell 5 (NFAT5) was depleted using siRNA. Extracellular hyperosmolarity triggered expression of VEGF-A, VEGF-D, and PlGF genes, and secretion of PlGF-2. Hypoosmolarity decreased PlGF gene expression. Hypoxia induced expression of VEGF-A, VEGF-B, VEGF-D, and PlGF genes. Extracellular hyperosmolarity and hypoxia produced additive PlGF gene expression. Both hyperosmolarity and hypoxia induced expression of KDR and FLT-4 receptor genes, while hyperosmolarity caused neuropilin-2 and hypoxia neuropilin-1 gene expression. The hyperosmotic, but not the hypoxic, PlGF gene expression was in part mediated by NFAT5. The expression of PlGF in RPE cells depends on the extracellular osmolarity. The data suggest that high consumption of dietary salt may exacerbate the angiogenic response of RPE cells in the hypoxic retina via transcriptional activation of various VEGF family member genes.

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Effects of Thrombin on RPE Cells Are Mediated by Transactivation of Growth Factor Receptors

Cited by 29 publications

References 42 publications

Cytotoxic Effects of Curcumin in Human Retinal Pigment Epithelial Cells

Cytotoxic Effects of Curcumin in Human Retinal Pigment Epithelial Cells

Intravitreal Ranibizumab for Choroidal Neovascularization With Large Submacular Hemorrhage in Age-Related Macular Degeneration

Osmotic induction of placental growth factor in retinal pigment epithelial cells in vitro: contribution of NFAT5 activity

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