Fibrinogen mediates platelet-polymorphonuclear leukocyte cooperation during immune-complex glomerulonephritis in rats.

Wu, Xiaobo; Helfrich, Miep; Horton, Michael A.; Feigen, Larry P.; Lefkowith, James B.

doi:10.1172/jci117459

Cited by 47 publications

(41 citation statements)

References 33 publications

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“…In NTN, deposition of fibrin and fibrinogen is observed in glomeruli, and inhibition of thrombosis prevents severe renal damage (25,26). We also confirmed less fibrin deposition in Gas6 -/-mice than in wild-type mice by electron microscopy (data not shown).…”

supporting

confidence: 64%

Essential role of Gas6 for glomerular injury in nephrotoxic nephritis

Yanagita¹,

Ishimoto²,

Arai³

et al. 2002

J. Clin. Invest.

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Growth-arrest specific gene 6 (Gas6) is a vitamin K-dependent growth factor for mesangial and epithelial cells. To investigate whether Gas6 is essential for progressive glomerular injury, we constructed Gas6 -/-mice and examined the role of Gas6 in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis. We found less mortality and proteinuria in Gas6 -/-mice than in wild-type mice following injection of nephrotoxic serum. Glomerular cell proliferation, glomerular sclerosis, crescent formation, and deposition of fibrin/fibrinogen in glomeruli were also reduced in Gas6 -/-mice. Furthermore, administering Gas6 -/-mice recombinant wild-type Gas6, but not Gas6 lacking a previously characterized N-terminal γ-carboxyl group, induced massive proteinuria, glomerular cell proliferation, and glomerulosclerosis, comparable to responses seen in wildtype mice. These data indicate that Gas6 induces glomerular cell proliferation in NTN and suggest that this factor contributes to glomerular injury and the progression of chronic nephritis. mice with heterologous nephrotoxic serum (NTS), which has reactivity to several glomerular cell and basement membrane antigens (10).In the studies reported here, we created Gas6 -/-mice and used them to examine the role of Gas6 in murine NTN. Our findings demonstrate that Gas6 is essential for the full expression of progressive glomerular injury in this model. MethodsConstruction of targeting vector. The mouse Gas6 gene was cloned from a 129/SvJ genomic library (Stratagene, La Jolla, California, USA) using a 0.2-kb cDNA fragment encompassing the initial ATG codon of mouse Gas6 as a probe (6). The 3.0-kb EcoRI-EcoRI and 3.5-kb BamHI-BamHI genomic fragments derived from the isolated clone were used for the construction of the targeting vector, along with a neomycin-resistance gene driven by the phosphoglycerate kinase-1 (Pgk-1) promoter (Pgk-neo r ) and a diphtheria toxin A-fragment gene driven by the MC1 promoter as positive and negative selection markers, respectively ( Figure 1) (11). Using this construct, homologous recombination results in the replacement of the EcoRI-BamHI genomic fragment that includes the translation starting codon in the Pgk-neo r cassette, resulting in abolition of Gas6 expression.Generation of Gas6 knockout mice. The embryonic stem cell line used in this study was E14 derived from 129/Ola mice. The targeting experiment and generation of mutant mice were performed as described previously (12). The germline chimera was backcrossed for 17 generations with C57BL/6 mice to obtain Gas6 +/-mice with a C57BL/6 background. The resulting Gas6 +/-F 17 mice were then intercrossed to generate the homozygous Gas6 -/-mice. Additional control inbred C57BL/6 mice were obtained from Shimizu Laboratory Animal Center (Hamamatsu, Japan). All mice were housed under specific pathogen-free conditions. All animal experiments were performed in accordance with institutional guidelines, and the Review Board of Kyoto University granted ethical permission to perform this...

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supporting

confidence: 64%

Essential role of Gas6 for glomerular injury in nephrotoxic nephritis

Yanagita¹,

Ishimoto²,

Arai³

et al. 2002

J. Clin. Invest.

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“…a M b 2 (Mac-1, CD11bCD18) is a principal neutrophil integrins, which, upon inflammatory challenges, undergoes conformational change for high affinity/avidity binding to its ligands, such as fibrinogen (Fg) and intercellular cell adhesion molecule-1 (ICAM-1, CD54). [8][9][10][11][12][13] The close proximity and the timing rendered by selectin-mediated leukocyte rolling are generally believed to facilitate b 2 -integrin activation by extracellular stimuli, such as interleukin-8 (IL-8), platelet activating factor (PAF), stromal cell-derived factor 1 (SDF-1, CXCL12) and several others. [14][15] They are released from and displayed on the activated endothelial lining of the vessel walls, which dynamically forms the "adhesive zone" with the contact site of rolling leukocytes in situ and locally activates leukocyte integrins in subseconds through pertussis toxin (PTX)-sensitive Gi-type heterotrimeric G-protein coupled receptors (GPCRs).…”

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confidence: 99%

P-selectin Cross-links PSGL-1 and Enhances Neutrophil Adhesion to Fibrinogen and ICAM-1 in a Src Kinase-Dependent, but GPCR-Independent Mechanism

Zhang

Geng

et al. 2007

Cell Adhesion & Migration

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“…From the earlier histopathological detection of fibrin in delayed-type hypersensitivity (1) and on tissue macrophages (2), recent experiments have demonstrated that systemic defibrinogenation drastically attenuates inflammatory responses to purulent bacterial infections (3), implanted biomaterials (4), and Ig-mediated acute nephrotoxic nephrites (5) in vivo.…”

Section: Introductionmentioning

confidence: 99%