Regulation of Pigment Epithelium–Derived Factor Production and Release by Retinal Glial (Müller) Cells under Hypoxia

Lange, Johannes; Yafai, Yousef; Reichenbach, Andreas; Wiedemann, Peter; Eichler, Wolfdietrich

doi:10.1167/iovs.08-2201

Cited by 46 publications

(41 citation statements)

References 48 publications

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“…45,62,63 PEDF can protect RGC from death after glutamate toxicity, ischemia, trophic factor withdrawal, and in mouse models of glaucoma and inherited retinal degeneration. 35,38,[64][65][66][67] In vitro and in vivo, optimal RGC neuroprotective dosages of PEDF were 2.5 3 10 À5 lg/lL and 1 lg/lL, respectively. Others report that in vivo, 0.001 lg/lL is required to protect RGC from excitotoxicity and serum withdrawal, 36 a concentration of PEDF that is also neuroprotective for photoreceptors, cerebellar granule cells, and hippocampal neurons.…”

Section: Discussionmentioning

confidence: 98%

“…13,21,28,29 Although major sources of PEDF are choroid, ciliary body, and corneal epithelium, constitutive expression is also detected in RGC and photoreceptors. [30][31][32][33][34][35][36] The upregulation of endogenous PEDF in activated Müller cells and astrocytes may become an RGC neuroprotective source of PEDF during the early stages of degenerative conditions. 13,34,35,37 Although the mechanisms underlying PEDFmediated neuroprotection remain unclear, PEDF does promote the survival of photoreceptors and RGC in many retinal pathologies.…”

mentioning

confidence: 99%

“…[30][31][32][33][34][35][36] The upregulation of endogenous PEDF in activated Müller cells and astrocytes may become an RGC neuroprotective source of PEDF during the early stages of degenerative conditions. 13,34,35,37 Although the mechanisms underlying PEDFmediated neuroprotection remain unclear, PEDF does promote the survival of photoreceptors and RGC in many retinal pathologies. 34,[38][39][40][41] In this present study, we evaluated, in vitro and in vivo, the RGC neuroprotective and axogenic properties of PEDF and compared the results with the effects of CNTF, a neurotrophic factor with well documented RGC survival and neurite/axon growth promoting properties.…”

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confidence: 99%

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Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Vigneswara¹,

Berry²,

Logan³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Vigneswara V, Berry M, Logan A, Ahmed Z. Pigment epithelium-derived factor is retinal ganglion cell neuroprotective and axogenic after optic nerve crush injury. Invest Ophthalmol Vis Sci. 2013;54: 262454: -263354: . DOI: 10.1167 PURPOSE. To investigate neuroprotective and axogenic properties of pigment epitheliumderived factor (PEDF) in retinal ganglion cells (RGC) in vitro and in vivo.METHODS. Adult rat retinal cultures were treated with combinations of PBS and PEDF with or without a cell permeable analogue of cAMP, and RGC survival and neurite lengths quantified. The optic nerves of anesthetised rats were also crushed intraorbitally to transect all RGC axons followed by intravitreal injections of either PBS, PEDF, or cAMPþPEDF every 7 days. RGC were back filled with FluoroGold to quantify RGC survival and longitudinal optic nerve sections were stained with GAP43 antibodies to detect regenerating RGC axons.RESULTS. An optimal dose of 2.5 3 10 À5 lg/lL, promoted 65% more RGC survival than controls in vitro, increasing by 4.4-and 5-fold the number of RGC with neurites and the mean neurite length, respectively. Addition of cAMP with or without PEDF did not potentiate RGC survival or the mean number of RGC with neurites, but enhanced RGC neurite length by 1.4-fold, compared with PEDF alone. After optic nerve crush (ONC), PEDF protected RGC from apoptosis and increased the numbers of regenerating RGC axons in the optic nerve by 4.6-and 3.4-fold, respectively when compared with controls. cAMP did not enhance PEDF-induced RGC neuroprotection, but potentiated its neuroregenerative effects by 2-to 3-fold, increasing the number of RGC axons regenerating at 500 and 1000 lm from the lesions site.CONCLUSIONS. This study is the first to demonstrate that PEDF enhances both RGC survival and axon regeneration in vitro and in vivo.Keywords: PEDF, retinal ganglion cells, neuroprotection, axon regeneration, optic nerve R etinal ganglion cells (RGC) rapidly die after axotomy, but are protected by combinatorial treatments with neurotrophic factors (NTF), including brain-derived NTF (BDNF), neurotrophin-3/4 (NT-3/4), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic (GDNF), and basic fibroblast growth factor (FGF2). 1-7 NTF combinations also activate intrinsic axon growth signalling pathways that initiate RGC axon regeneration.1-7 Pigment epithelium-derived factor (PEDF) is a 50 kDa NTF glycoprotein belonging to the serpin superfamily, that protects a wide range of central nervous system (CNS) neurons. [8][9][10][11][12][13][14][15] Although first isolated from fetal human retinal pigment (choroid) epithelial cells, like many other NTF, PEDF is expressed in a wide variety of tissues including brain, spinal cord, skeletal muscle, heart, endothelial cells, and osteoblasts. [16][17][18][19][20] PEDF has an array of unique properties including neuroprotective, anti-angiogenic, antiinflammatory, anti-oxidative, and antitumorigenic activities. [21][22][23][24][25][26][27] PEDF is a multifaceted NTF that ...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Vigneswara¹,

Berry²,

Logan³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…There is evidence that PEDF protein levels are positively correlated with oxygen tension as it is downregulated in ischemic and hypoxic retinal glial (Müller) cells as well as in anoxic cardiac myocytes. 29,30 In this study, we could extend the regulation of PEDF by hypoxia to human adipocytes, in which hypoxia represses PEDF expression and release. This repression occurs not in such a prominent manner as in anoxic cardiac myocytes, in which a repression of about 40-50% was observed.…”

Section: Discussionmentioning

confidence: 99%

“…30 However, similar to the effects in retinal glial (Müller) cells, we also observed a reduction of PEDF release of about 15-20% under 1% oxygen. 29 As PEDF is a substrate for metalloproteinase-2 (MMP-2) and MMP-9 and MMPs are upregulated at low oxygen concentrations, reduced levels of PEDF under hypoxia may be because of the post-translational degradation through hypoxia induced MMPs. 31 We also found elevated levels of MMPs after adipocyte treatment with 1% of oxygen (data not shown) so that the downregulation found by us may also underlie a mechanism of degradation of PEDF by MMPs.…”

Section: Discussionmentioning

confidence: 99%

Pigment epithelium-derived factor (PEDF) is one of the most abundant proteins secreted by human adipocytes and induces insulin resistance and inflammatory signaling in muscle and fat cells

et al. 2010

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Objective: Pigment epithelium-derived factor (PEDF) is a multifunctional protein with neurotrophic and anti-angiogenic properties. More recently it became evident that PEDF is upregulated in patients with type 2 diabetes and also contributes to insulin resistance in mice. During characterization of the secretome of in vitro differentiated human adipocytes by two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization-MS, we found that PEDF is one of the most abundant proteins released by adipocytes. The aim of this study was to investigate the regulation and autocrine function of PEDF in human adipocytes and to determine its paracrine effects on human skeletal muscle cells (hSkMC) and human smooth muscle cells (hSMC). Methods and results: Human primary adipocytes secrete 130 ng ml À1 PEDF over 24 h from 1 million cells, which is extremely high as compared with adiponectin, interleukin-6 (IL-6) or IL-8. This release of PEDF is significantly higher than from other primary cells, such as adipose-tissue located macrophages (50-times), hSkMC and hSMC (5-times). PEDF protein expression significantly increases during adipogenesis, which is paralleled by increased PEDF secretion. Furthermore, tumor necrosis factor-a and hypoxia significantly downregulate PEDF protein levels. PEDF secretion was significantly reduced by troglitazone and hypoxia and significantly increased by insulin. Treatment of adipocytes and hSkMC with PEDF induced insulin resistance in adipocytes, skeletal and smooth muscle cells at the level of insulin-stimulated Akt phosphorylation, which was dose dependent and more prominent in adipocytes. Furthermore, inflammatory nuclear factor-kB (NF-kB) signaling was induced by PEDF. In hSMC, PEDF induced proliferation (1.7-fold) and acutely activated proliferative and inflammatory signaling pathways (NF-kB, p38 mitogen-activated protein kinase and mammalian target of rapamycin). Conclusion: PEDF is one of the most abundant adipokines and its secretion is inversely regulated by insulin and hypoxia. PEDF induces insulin resistance in adipocytes and hSkMC and leads to inflammatory signaling in hSMC. Because of these diverse actions, PEDF is a key adipokine, which could have an important role in diabetes and obesity-related disorders.

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Müller glial cells inhibit proliferation of retinal endothelial cells via TGF‐β2 and Smad signaling

Yafai

Iandiev

Lange

et al. 2014

Glia

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Neovascularization is a sight-threatening complication of ischemic proliferative retinopathies. Transforming growth factor (TGF)-β, a cytokine with multiple functions in the retina, participates in the control of pathological angiogenesis and neovascularization. Retinal glial (Müller) cells produce TGF-β2 under physiological and post-ischemic conditions. To characterize glial cell-derived mediators of angiogenesis regulation in glial-endothelial interactions in the retina, we co-cultured primary Müller cells and bovine microvascular retinal endothelial cells (BRECs). Müller cell-derived TGF-β2 was bound by the BRECs, which were found to express serine/threonine kinase TGF-β receptors, and stimulated TGF-β-dependent anti-proliferative signaling pathways. The proliferation of BRECs was attenuated by exogenous TGF-β2 as well as by the presence of Müller cell culture media. The following intracellular signaling mechanisms were found to be involved in the anti-angiogenic action of Müller cell-derived TGF-β2: (i) binding of TGF-β2 to BRECs is mediated by the type-II TGF-β receptor, leading to (ii) activation and phosphorylation of receptor-activated Smads; (iii) Müller cell-derived TGF-β2 activates Smad2 and Smad3 to (iv) attenuate the phosphorylation state of the MAP kinases, extracellular signal-regulated kinase (ERK)-1/-2. Neutralizing TGF-β or TGF-β type-II receptor or blocking the activation of Smads partially abrogated the effect of Müller cell-conditioned media on BRECs. Together, our data suggest that Müller cells release TGF-β2, inhibiting the proliferation of retinal endothelial cells via activation of Smad2/Smad3 and attenuation of ERK signaling. Given the context-dependent action of TGF-β2 on angiogenesis, our results may have implications for understanding the pathogenesis of retinal angiopathies, such as diabetic retinopathy, and the anti-angiogenic role of TGF-β therein.

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Regulation of Pigment Epithelium–Derived Factor Production and Release by Retinal Glial (Müller) Cells under Hypoxia

Cited by 46 publications

References 48 publications

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Pigment epithelium-derived factor (PEDF) is one of the most abundant proteins secreted by human adipocytes and induces insulin resistance and inflammatory signaling in muscle and fat cells

Müller glial cells inhibit proliferation of retinal endothelial cells via TGF‐β2 and Smad signaling

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