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(American Journal of Pathology. 2006;168:1413-1424.)
© 2006 American Society for Investigative Pathology

Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

Kent Doi^*, Koji Okamoto^*, Kousuke Negishi^*, Yoshifumi Suzuki^*, Akihide Nakao^*, Toshiro Fujita^*, Akiko Toda^*, Takehiko Yokomizo, Yoshihiro Kita, Yasuyuki Kihara, Satoshi Ishii, Takao Shimizu and Eisei Noiri^*

From the Departments of Nephrology and Endocrinology,^* and Biochemistry and Molecular Biology, and the Center for NanoBio Integration, University of Tokyo, Tokyo, Japan

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- 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.

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