TY - JOUR
T1 - Attenuation of folic acid-induced renal inflammatory injury in platelet-activating factor receptor-deficient mice
AU - Doi, Kent
AU - Okamoto, Koji
AU - Negishi, Kousuke
AU - Suzuki, Yoshifumi
AU - Nakao, Akihide
AU - Fujita, Toshiro
AU - Toda, Akiko
AU - Yokomizo, Takehiko
AU - Kita, Yoshihiro
AU - Kihara, Yasuyuki
AU - Ishii, Satoshi
AU - Shimizu, Takao
AU - Noiri, Eisei
N1 - Funding Information:
Supported in part by grants from the Cell Science Research Foundation, Osaka, Japan (to E.N.); the Araki Memorial Research Foundation for Medicine and Biochemistry, Tokyo, Japan (to E.N.); Takeda Medical Science, Osaka, Japan (to E.N.); and the Health and Labour Science research grants for Research on Human Genome, Tissue Engineering, and Food Biotechnology from the Ministry of Health, Labour, and Welfare of Japan (to E.N.).
PY - 2006/5
Y1 - 2006/5
N2 - 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 fblic 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-α 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 PAJF 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 fblic 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.
AB - 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 fblic 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-α 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 PAJF 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 fblic 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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U2 - 10.2353/ajpath.2006.050634
DO - 10.2353/ajpath.2006.050634
M3 - Article
C2 - 16651609
AN - SCOPUS:33646534443
VL - 168
SP - 1413
EP - 1424
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 5
ER -