TY - JOUR
T1 - Increased 5-lipoxygenase activating protein in immune-mediated experimental nerphritis
AU - Montero, Angel
AU - Uda, Susumu
AU - Kelavkar, Uddhav
AU - Yoshimura, Ashio
AU - Badr, Kamal F.
AU - Munger, Karen A.
PY - 2003/9
Y1 - 2003/9
N2 - Background: The binding of 5-lipoxygenase (5-LO) to 5-LO activating protein (FLAP) is a prerequisite for subsequent formation of leukotrienes from arachidonic acid. Methods: We investigated the localization of FLAP in a rat model of accelerated anti-glomerular basement membrane nephritis and protein expression in cultured rat glomerular endothelial cells. Results: As expected, 5-LO staining was intense and localized exclusively to perinuclear region and inside the nucleus of leukocytes and macrophages. In these cells, FLAP immunoreactivity co-localized with that of 5-LO, and was restricted to nuclear envelope. Surprisingly, intense nuclear and cytoplasmic staining for FLAP was also observed in glomerular endothelial cells in early experimental glomerulonephritis. Although 5-LO and FLAP mRNA were detected in cultured rat glomerular endothelial cells by RT-PCR, Western blot revealed only FLAP and no 5-LO protein. FLAP protein was regulated in glomerular endothelial cells by the proinflammatory cytokine, interferon-γ, in a dose-dependent manner. Conclusion: The unexpected discovery of FLAP in glomerular endothelial cells in this model of glomerulonephritis, coupled with our demonstration that oral FLAP antagonist therapy reduces proteinuria in human glomerulonephritis and animal models of diabetes, provides further impetus to examine the role of this pro-inflammatory protein in glomerular immune injury.
AB - Background: The binding of 5-lipoxygenase (5-LO) to 5-LO activating protein (FLAP) is a prerequisite for subsequent formation of leukotrienes from arachidonic acid. Methods: We investigated the localization of FLAP in a rat model of accelerated anti-glomerular basement membrane nephritis and protein expression in cultured rat glomerular endothelial cells. Results: As expected, 5-LO staining was intense and localized exclusively to perinuclear region and inside the nucleus of leukocytes and macrophages. In these cells, FLAP immunoreactivity co-localized with that of 5-LO, and was restricted to nuclear envelope. Surprisingly, intense nuclear and cytoplasmic staining for FLAP was also observed in glomerular endothelial cells in early experimental glomerulonephritis. Although 5-LO and FLAP mRNA were detected in cultured rat glomerular endothelial cells by RT-PCR, Western blot revealed only FLAP and no 5-LO protein. FLAP protein was regulated in glomerular endothelial cells by the proinflammatory cytokine, interferon-γ, in a dose-dependent manner. Conclusion: The unexpected discovery of FLAP in glomerular endothelial cells in this model of glomerulonephritis, coupled with our demonstration that oral FLAP antagonist therapy reduces proteinuria in human glomerulonephritis and animal models of diabetes, provides further impetus to examine the role of this pro-inflammatory protein in glomerular immune injury.
KW - Five-lipoxygenase activating protein
KW - Glomerular endothelial cells
KW - Glomerulonephritis
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M3 - Article
C2 - 14733414
AN - SCOPUS:1442356451
SN - 1121-8428
VL - 16
SP - 682
EP - 690
JO - Journal of Nephrology
JF - Journal of Nephrology
IS - 5
ER -