Thy-1 Antigen Mediates Apoptosis of Rat Glomerular Cells in vitro and in vivo

Morita, Hiroyuki; Isobe, Ken‐ichi; Cai, Zhe; Miyazaki, Takashi; Matsumoto, Yoshinari; Shinzato, Toru; Yoshikai, Yasunobu; Kimata, Koji; Maeda, Kayaho

doi:10.1159/000189054

Cited by 26 publications

(5 citation statements)

References 11 publications

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“…Recent studies indicate that apoptosis is triggered in rat cultured mesangial cells in vitro after 12–24 h of exposure to anti-Thy-1.1 antibody without complement activation [18, 19]. However, apoptosis of nuclei in the present study was prevented by depletion of complement, although abundant anti-Thy-1.1 antibody deposited on mesangial cells.…”

Section: Discussioncontrasting

confidence: 77%

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Complement-Mediated Killing of Mesangial Cells in Experimental Glomerulonephritis: Cell Death by a Combination of Apoptosis and Necrosis

Shimizu

Masuda²,

Kitamura³

et al. 2000

Nephron

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Immune system mediated, particularly antibody- and complement-mediated, glomerular injury triggers glomerulonephritis (GN). To characterize complement-mediated cytotoxicity in GN, we assessed the process of mesangial cell death induced by C5b-9 attack in Thy-1 GN. Cell injury was recognized morphologically, and nuclear DNA breaks were confirmed by the DNA nick end labeling (TUNEL) method as well as DNA gel electrophoresis. Thy-1 GN was induced in rats with anti-Thy-1.1 antibody injection. Mouse IgG (administered antibody) and rat C3 were detected in all glomeruli within 5 min after antibody injection. Damaged mesangial cells with condensed as well as TUNEL-positive nuclei could be observed at 20 min and became prominent at 40–60 min. Ultrastructurally, damaged mesangial cells contained condensed apoptotic nuclei from 40 to 60 min, whereas the cytoplasm showed necrotic degeneration. This was followed by progressive lysis of both nuclei and cytoplasm. The DNA ‘ladder’ pattern was observed by gel electrophoresis of extracted DNA between 40 and 60 min and correlated with the increased number of TUNEL-positive damaged mesangial cells. To examine the role of complement in this form of cell death, complement depletion was induced in rats by cobra venom factor. Complement-depleted rats showed no rat C3 deposition, rare TUNEL-positive mesangial cells, rare ultrastructural degenerated mesangial cells with apoptotic nuclei and necrotic cytoplasm, and no DNA ‘ladder’ pattern on gel electrophoresis at 40 min, although prominent mouse IgG was seen in glomeruli. To analyze milder forms of complement injury, a low dose of the antibody was administered to rats with a normal complement level. A few TUNEL-positive mesangial cells were detected in the glomeruli which contained apoptotic nuclei and necrotic cytoplasm. Our results indicate that an apoptotic death mechanism accompanies cell necrosis in complement-mediated mesangial cell destruction in GN and that this unusual form of cell death may represent a combination of apoptosis-necrosis within the same cell. Complement injury activates a ‘death program’ which in turn leads to irreversible damage of mesangial cells and which may contribute to initiation and development of GN.

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Section: Discussioncontrasting

confidence: 77%

“…Rat kidneys were harvested and glomeruli isolated by the standard three-stage sieving method [18, 19]. Briefly, diced renal cortices were sequentially filtered through a series of stainless steel sieves, measuring, respectively, 125, 173, and 53 µm.…”

Section: Methodsmentioning

confidence: 99%

Complement-Mediated Killing of Mesangial Cells in Experimental Glomerulonephritis: Cell Death by a Combination of Apoptosis and Necrosis

Shimizu

Masuda²,

Kitamura³

et al. 2000

Nephron

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“…Crosslinking antibodies to THY1 induce apoptosis in thymocytes and mesangial cells (Ref. 157, 158). Fibroblasts lacking THY1 expression are resistant to apoptosis when they contract collagen gels, even though they are more contractile.…”

Section: Myofibroblast Survival/apoptosismentioning

confidence: 99%

Myofibroblast differentiation and survival in fibrotic disease

Kis

Liu

Hagood

2011

Expert Rev. Mol. Med.

192

160

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During wound healing, contractile fibroblasts called myofibroblasts regulate the formation and contraction of granulation tissue; however, pathological and persistent myofibroblast activation, such as occurs in hypertrophic scars or tissue fibrosis, results in loss of function. Many outstanding reviews outline cellular and molecular features of myofibroblasts, and their roles in a variety of diseases. This review will focus on the origins of myofibroblasts and the factors which control their differentiation and prolonged survival in fibrotic tissues. Pulmonary fibrosis is used to illustrate many key points, but examples from other tissues and models are also included. Myofibroblasts emerge mostly from tissue-resident fibroblasts but also from epithelial, endothelial cells or other mesenchymal precursors. Their differentiation is influenced by cytokines, growth factors, extracellular matrix composition and stiffness, and cell surface molecules such as proteoglycans and THY1, among other factors. Many of these effects are modulated by cell contraction. Myofibroblasts resist programmed cell death, promoting their accumulation in fibrotic tissues. The cause of resistance to apoptosis in myofibroblasts is under ongoing investigation, but many of the same stimuli that regulate their differentiation are involved. The contributions of oxidative stress, the WNT - β-catenin pathway and PPARγ to myofibroblast differentiation and survival are increasingly appreciated.

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“…Thy-1.1 nephritis is an established experimental model for human mesangial proliferative GN [29, 30], and self-limiting mesangial hypercellularity is seen after the injection of the Thy-1.1 antibody [23, 29]. In this model, MC apoptosis is important in the initiation [31]and resolution [32, 33]phases for the clearance of MCs. However, little is known about the effect of GC on mesangial hypercellularity, especially on the induction of apoptosis, in this model.…”

Section: Introductionmentioning

confidence: 99%

Methylprednisolone Accelerates the Resolution of Glomerulonephritis by Sensitizing Mesangial Cells to Apoptosis

Maruyama¹,

Kashihara²,

Yamasaki³

et al. 2001

Nephron Exp Nephrol

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Glucocorticoid has long been used to treat patients with glomerulonephritis because it ameliorates mesangial cell proliferation and proteinuria, in part by suppressing nuclear factor-kappa B (NF-ĸB) activation, which regulates the transcription of various pro-inflammatory genes. Recent evidence shows that NF-ĸB activation increases the resistance to TNF-α-induced apoptosis in mesangial cells. We examined glomerular cell proliferation and apoptosis along with NF-ĸB activation in the Thy-1.1 nephritis model. We also evaluated TNF-α-induced apoptosis in cultured mesangial cells. Methylprednisolone treatment ameliorated mesangial hypercellularity in Thy-1.1 nephritis by decreasing proliferating cells and increasing apoptosis in the glomeruli. These effects were associated with suppressed NF-ĸB activation. This in vitro study revealed that treatment with methylprednisolone and TNF-α induced cultured mesangial cell apoptosis. These results suggest that methylprednisolone may accelerate the resolution phase of Thy-1.1 nephritis in part by sensitizing mesangial cells to apoptosis.

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Thy-1 Antigen Mediates Apoptosis of Rat Glomerular Cells in vitro and in vivo

Cited by 26 publications

References 11 publications

Complement-Mediated Killing of Mesangial Cells in Experimental Glomerulonephritis: Cell Death by a Combination of Apoptosis and Necrosis

Complement-Mediated Killing of Mesangial Cells in Experimental Glomerulonephritis: Cell Death by a Combination of Apoptosis and Necrosis

Myofibroblast differentiation and survival in fibrotic disease

Methylprednisolone Accelerates the Resolution of Glomerulonephritis by Sensitizing Mesangial Cells to Apoptosis

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