Attenuation of folic acid-induced renal inflammatory injury in platelet-activating factor receptor-deficient mice.

Abstract

Platelet-activating factor (PAF), a potent lipid mediator with various biological activities, plays an important role in inflammation by recruiting leukocytes. In this study we used platelet-activating factor receptor (PAFR)-deficient mice to elucidate the role of PAF in inflammatory renal injury induced by folic acid administration. PAFR-deficient mice showed significant amelioration of renal dysfunction and pathological findings such as acute tubular damage with neutrophil infiltration, lipid peroxidation observed with antibody to 4-hydroxy-2-hexenal (day 2), and interstitial fibrosis with macrophage infiltration associated with expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha in the kidney (day 14). Acute tubular damage was attenuated by neutrophil depletion using a monoclonal antibody (RB6-8C5), demonstrating the contribution of neutrophils to acute phase injury. Macrophage infiltration was also decreased when treatment with a PAF antagonist (WEB2086) was started after acute phase. In vitro chemotaxis assay using a Boyden chamber demonstrated that PAF exhibits a strong chemotactic activity for macrophages. These results indicate that PAF is involved in pathogenesis of folic acid-induced renal injury by activating neutrophils in acute phase and macrophages in chronic interstitial fibrosis. Inhibiting the PAF pathway might be therapeutic to kidney injury from inflammatory cells.

• Authors: Kent Doi, Koji Okamoto, Kousuke Negishi, Yoshifumi Suzuki, Akihide Nakao, Toshiro Fujita, Akiko Toda, Takehiko Yokomizo, Yoshihiro Kita, Yasuyuki Kihara, Satoshi Ishii, Takao Shimizu, Eisei Noiri
• Journal: The American journal of pathology (Am J Pathol) Vol. 168 Issue 5 Pg. 1413-24 (May 2006) ISSN: 0002-9440 [Print] United States
• PMID: 16651609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Platelet Activating Factor
• Platelet Membrane Glycoproteins
• Reactive Oxygen Species
• Receptors, G-Protein-Coupled
• Tumor Necrosis Factor-alpha
• platelet activating factor receptor
• Folic Acid

Topics

• Animals
• Chemokine CCL2 (metabolism)
• Chemotaxis (physiology)
• Fibrosis
• Folic Acid
• Inflammation (chemically induced, metabolism)
• Kidney Diseases (chemically induced, immunology, metabolism)
• Leukocytes (immunology, metabolism)
• Macrophages (pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Neutrophils (immunology, metabolism)
• Platelet Activating Factor (antagonists & inhibitors, metabolism)
• Platelet Membrane Glycoproteins (antagonists & inhibitors, genetics)
• Reactive Oxygen Species (metabolism)
• Receptors, G-Protein-Coupled (antagonists & inhibitors, genetics)
• Time Factors
• Tumor Necrosis Factor-alpha (metabolism)