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

Am J Pathol. 2006 May;168(5):1413-24. doi: 10.2353/ajpath.2006.050634.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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