Intraglomerular platelet aggregation and experimental glomerulonephritis

Abstract

Oxygen free radical production inhibits ADPase-mediated antithrombotic action. Different forms of experimental glomerulonephritis (GN) are characterized by early glomerular influx of inflammatory cells and thrombus formation. The causal relationship of these inflammatory events is obscure. Previous studies have shown that glomerular ADPase in the rat kidney may function as a potent antithrombotic principle, whereas this enzyme is highly sensitive for oxygen free radicals. To study whether O2- producing inflammatory cells are able to induce intraglomerular thrombosis via impairment of ADPase, we investigated influx of inflammatory cells in relation to glomerular ADPase activity and platelet aggregation in three models of GN. In two of these models (anti-Thy1 and anti-GBM GN) influx of neutrophils and thrombus formation occurs, whereas in anti-FX1A nephritis this aspect of the inflammatory phase is not present. The results show a relationship between influx of oxygen free radical-producing cells, reduction of glomerular ADPase activity and increased platelet aggregation. Moreover, it is shown that impairment of glomerular ADPase and increased platelet aggregation in anti-Thy1 and anti-GBM GN could be reduced by treatment with superoxide dismutase and catalase. The demonstration that activated neutrophils perfused ex vivo in the rat kidney can directly affect glomerular ADPase and antithrombotic potential in an O2- dependent manner, further supports the proposed sequence of events; oxygen free radicals produced by activated neutrophils reduce glomerular ADPase activity, leading to facilitation of thrombus formation.

Infusion of platelet-derived growth factor or basic fibroblast growth factor induces selective glomerular mesangial cell proliferation and matrix accumulation in rats.

“…A second possibility is that the injected anti-Thy 1.1 antibody might induce glomerular leukocyte or platelet influx via increased release of chemoattractants or increases of the local procoagulant activity (48,49). Both leukocytes and platelets contain potent mesangial cell growth factors ( 1, 4).…”

Oxidants in Chronic Kidney Disease

“…Enhanced generation of oxidants has been demonstrated in anti-Thy 1.1 and anti-GBM-induced glomerulonephritis with cytochemical techniques (12) and in isolated glomeruli (13) or macrophages (13,14). Several immune reactants, such as serumtreated zymosan (a C 3 b receptor stimulus), heat-aggregated IgG (an Fc receptor stimulus), immune complexes, complement components, and antinuclear antibody (15) all have been shown to trigger the oxidative burst.…”

The Antiproliferative Drug Doxorubicin Inhibits Liver Fibrosis in Bile Duct-Ligated Rats and Can Be Selectively Delivered to Hepatic Stellate Cells in Vivo

“…Moreover, evaluation of DAB stainings revealed that the number of reactive oxygen species-producing cells was also increased in the livers of DOX-treated rats (Table 1). These DAB-positive cells consisted mainly of neutrophils, judged by the presence of polymorphic nuclei in these cells after evaluation of HE-stained liver sections and based on previous studies (Poelstra et al, 1990).…”

“…General toxicity was monitored by analysis of body weight (BW), whereas intrahepatic toxicity of DOX toward liver cells was examined by analysis of serum AST, ALT, AP, and ␥-GT levels. Inflammatory cell influx in the livers was assessed by diaminobenzidine (DAB) staining as described previously, as well as by evaluation of hematoxylin/eosin-stained liver sections (Poelstra et al, 1990;Greupink et al, 2005). To evaluate the effect of DOX on the bile duct epithelial cell proliferation, staining with a monoclonal antibody raised against cytokeratin 7 (Santa Cruz Biotechnology, Santa Cruz, CA) was performed, according to standard indirect immunohistochemical techniques.…”