High glucose modulates P2X 7 receptor-mediated function in human primary fibroblasts

Solini, Anna; Chiozzi, Paola; Falzoni, Simonetta; Morelli, Anna; Fellin, Renato; Virgilio, Francesco Di

doi:10.1007/s001250051520

Cited by 56 publications

(48 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5, B-D). The activation of P2X 7 receptor also triggers plasma membrane depolarization caused by transmembrane cation influx (25). Therefore we monitored the change in membrane potential using a fluorescent potentialsensitive anionic dye, DiBAC 4 (3).…”

Section: P2x 7 Receptor-induced Cell Death Is Mediated By CLmentioning

confidence: 99%

Involvement of Chloride in Apoptotic Cell Death Induced by Activation of ATP-sensitive P2X7 Purinoceptor

Tsukimoto

Hishida

Ikari

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

The ATP-gated P2X 7 receptor is a plasma membrane receptor belonging to the family of P2X purinoceptors. Its activation leads to multiple downstream events including influx of ions, pore formation to allow the passage of larger molecular weight species, and cell death by apoptosis and/or necrosis. The cell death is thought to be correlated with the pore formation but does not directly result from the dilatation of pores. We have generated and characterized a clone of chicken DT40 lymphocytes stably transfected with the rat P2X 7 receptor. In this study, we investigated the mechanism of P2X 7 receptor-induced cell death using this clone. Treatment with P2X 7 receptor agonist, 2-3-O-(4-benzoylbenzoyl)-ATP induced depolarization of membrane potential, pore formation, and cell shrinkage, an early hallmark of apoptosis in the buffer containing physiological concentrations of ions. Analysis by flow cytometry revealed that the activity of pore formation in shrunk cells was much higher than in non-shrunk cells. The activation of P2X 7 receptor also caused the release of lactate dehydrogenase from cells. The P2X 7 receptormediated cell shrinkage and lactate dehydrogenase release were blocked when media Cl ؊ was replaced with gluconate. However, removal of extracellular Cl ؊ did not affect plasma membrane depolarization and pore formation by treatment with 2-3-O-(4-benzoylbenzoyl)-ATP. Therefore we concluded that pore formation plays a critical role in the P2X 7 receptor-induced apoptotic cell death and that this is mediated by extracellular Cl ؊ influx.Extracellular ATP plays an important role in cell signaling, modulation of cell growth, differentiation, and induction of cell death by apoptosis and/or necrosis (1, 2). The actions of extracellular ATP are mediated through P2 purinoceptors, which are classified into two major subtypes: ionotropic P2X and metabotropic G protein-coupled P2Y receptors (3, 4). The P2X 7 receptor, previously designated as P2Z receptor and now the seventh member of P2X receptors, utilizes extracellular ATP to increase cationic permeability with consecutive plasma membrane depolarization, and its intense or prolonged activation leads to the opening of a large non-selective pore allowing the passage of hydrophilic molecules of up to 900 Da in size. This receptor shares 35-40% homology with other members of the P2X family, all with the same predicted topology of two transmembrane regions, a cysteine-rich extracellular loop, and intracellular N and C termini. The C terminus is more than 100 amino acids longer than that of any other member of the family and is essential for the opening of the large pore (5). The activation of the P2X 7 receptor has been reported to link to a number of other cellular events including cell fusion (6), membrane blebbing (7), and interleukin-1␤ release (8). The P2X 7 receptor was first cloned from rat brain (5) and subsequently from human monocytes (9) and mouse microglial cells (10

show abstract

Section: P2x 7 Receptor-induced Cell Death Is Mediated By CLmentioning

confidence: 99%

Involvement of Chloride in Apoptotic Cell Death Induced by Activation of ATP-sensitive P2X7 Purinoceptor

Tsukimoto

Hishida

Ikari

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Its systemic concentrations are used as a marker for adverse prognosis [8]. Fibroblasts are not only the major contributor to collagen biosynthesis, but also participate in plaque remodelling via expression and release of MMP2 and MMP9 [9]; moreover, they release abundant amounts of IL6, particularly in the presence of high glucose concentrations [10]. It has been repeatedly shown that primary skin fibroblasts exhibit at least some of the characteristics and functional properties of vascular wall cells [11,12] and share with them a common genesis [13].…”

Section: Introductionmentioning

confidence: 99%

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

et al. 2006

Self Cite

View full text Add to dashboard Cite

Aims/hypothesis Atherosclerosis is particularly aggressive in patients with diabetes. Hyperhomocysteinaemia causes oxidative stress and cytokine secretion: its atherogenic effect is mediated by an enhanced inflammatory response. Matrix metalloproteinases (MMPs) regulate extracellular matrix degradation and remodelling, and contribute to the vulnerability of the atherosclerotic lesion. Fibroblasts contribute to collagen biosynthesis and participate in plaque remodelling via expression and release of MMP2 and MMP9. To explore the role of hyperhomocysteinaemia in cellular pathways involved in plaque growth and stability in diabetic patients, we studied the effect of hyperhomocysteinaemia in human fibroblasts grown in the presence of normal or high glucose concentrations. Materials and methods In fibroblasts of five normal subjects, grown at 5.5 or 22 mmol/l glucose and treated with homocysteine, we determined: (1) MMP2, MMP9 and tissue inhibitor of metalloproteinases (TIMP)-1 (an MMP inhibitor) production by western blot analysis; (2) their activity by zymography; (3) TGFB1 expression by real-time PCR; and (4) TGFB, fibronectin and IL6 release by ELISA. Results Hyperhomocysteinaemia increased the production and enzymatic activity of MMP2 and MMP9, the effect being more pronounced in high glucose. Conversely, TIMP1 production was reduced by hyperhomocysteinaemia in both conditions, especially in high glucose. Hyperhomocysteinaemia also stimulated IL6 release, at least in part through nuclear factor-κB activation. TGFB1 expression was not affected by hyperhomocysteinaemia either in normal or in high glucose. Conclusions/interpretation Homocysteine upregulates the MMP-TIMP pathway and IL6 release, the effect being stronger in the presence of high glucose. These actions of homocysteine may contribute to the increased atherogenesis observed in diabetic patients with poor metabolic control.

show abstract

“…High concentrations of glucose potentiate these P2X7-mediated responses [84] . This effect of glucose is attributed to a redistribution of P2X7 on the cell surface rather than increased expression of this receptor [84] . Of note, skin fibroblasts from type 2 diabetic subjects demonstrate enhanced P2X7-mediated responses compared to skin fibroblasts from normal subjects [85] .…”

Section: Fibroblastsmentioning

confidence: 99%

“…Human skin fibroblasts express P2X7 [83,84] . In addition to cation fluxes, dye uptake and membrane depolarisation, P2X7 activation in these cells results in microvesiculation, process elongation, IL-6 release and apoptosis [84] . High concentrations of glucose potentiate these P2X7-mediated responses [84] .…”

Section: Fibroblastsmentioning

confidence: 99%

“…In addition to cation fluxes, dye uptake and membrane depolarisation, P2X7 activation in these cells results in microvesiculation, process elongation, IL-6 release and apoptosis [84] . High concentrations of glucose potentiate these P2X7-mediated responses [84] . This effect of glucose is attributed to a redistribution of P2X7 on the cell surface rather than increased expression of this receptor [84] .…”

Section: Fibroblastsmentioning

confidence: 99%

See 1 more Smart Citation

P2X7 receptor in skin biology and diseases

Geraghty¹,

Watson²,

Adhikary³

et al. 2016

WJD

View full text Add to dashboard Cite

The P2X7 receptor is a trimeric ligand-gated cation channel present on immune and other cells. Activation of this receptor by its natural ligand extracellular adenosine triphosphate results in a variety of downstream responses, including the release of pro-inflammatory mediators and cell death. In normal skin, P2X7 is present on keratinocytes, Langerhans cells and fibroblasts, while the presence of this receptor on other cutaneous cells is mainly inferred from studies of equivalent cell types present in other tissues. Mast cells in normal skin however express negligible amounts of P2X7, which can be upregulated in cutaneous disease. This review discusses the potential significance of P2X7 in skin biology, and the role of this receptor in inflammatory skin disorders such as irritant and chronic dermatitis, psoriasis, graft-versus-host disease, as well is in wound healing, transplantation and skin cancer. AbstractThe P2X7 receptor is a trimeric ligand-gated cation channel present on immune and other cells. Activation of this receptor by its natural ligand extracellular adenosine triphosphate results in a variety of downstream responses, including the release of pro-inflammatory mediators and cell death. In normal skin, P2X7 is present on keratinocytes, Langerhans cells and fibroblasts, while the presence of this receptor on other cutaneous cells is mainly inferred from studies of equivalent cell types present in other tissues. Mast cells in normal skin however express negligible amounts of P2X7, which can be upregulated in cutaneous disease. This review discusses the potential significance of P2X7 in skin biology, and the role of this receptor in inflammatory skin disorders such as irritant and chronic dermatitis, psoriasis, graft-versus-host disease, as well is in wound healing, transplantation and skin cancer. Core tip: The P2X7 receptor is present on immune, stromal and epithelial cells. Activation of this receptor by its natural ligand, extracellular adenosine triphosphate, causes a variety of downstream effects including release of inflammatory mediators and growth factors, as well as cell death. P2X7 has various functions on skin cells, and studies of mouse models of disease and of human cells and tissues highlight emerging roles for this receptor in common skin disorders.

show abstract

High glucose modulates P2X 7 receptor-mediated function in human primary fibroblasts

Cited by 56 publications

References 25 publications

Involvement of Chloride in Apoptotic Cell Death Induced by Activation of ATP-sensitive P2X7 Purinoceptor

Involvement of Chloride in Apoptotic Cell Death Induced by Activation of ATP-sensitive P2X7 Purinoceptor

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

P2X7 receptor in skin biology and diseases

Contact Info

Product

Resources

About