PPAR{alpha} attenuates the proinflammatory response in activated mesangial cells.
The activated mesangial cell is an important therapeutic target for the control of glomerulonephritis. The peroxisome proliferator-activated receptor alpha (PPARalpha) has attracted considerable attention for its anti-inflammatory effects; however, its roles in the mesangial cells remain unknown. To determine the anti-inflammatory function of PPARalpha in mesangial cells, wild-type and Ppara-null cultured mesangial cells were exposed to lipopolysaccharide (LPS). LPS treatment caused enhanced proinflammatory responses in the Ppara-null cells compared with wild-type cells, as revealed by the induction of interleukin-6, enhanced cell proliferation, and the activation of the nuclear factor (NF)-kappaB signaling pathway. In wild-type cells resistant to inflammation, constitutive expression of PPARalpha was undetectable. However, LPS treatment induced the significant appearance and substantial activation of PPARalpha, which would attenuate the proinflammatory responses through its antagonizing effects on the NF-kappaB signaling pathway. The induction of PPARalpha was coincident with the appearance of alpha-smooth muscle actin, which might be associated with the phenotypic changes of mesangial cells. Moreover, another examination using LPS-injected wild-type mice demonstrated the appearance of PPARalpha-positive cells in glomeruli, suggesting in vivo correlation with PPARalpha induction. These results suggest that PPARalpha plays crucial roles in the attenuation of inflammatory response in activated mesangial cells. PPARalpha might be a novel therapeutic target against glomerular diseases.
Kono
Keiichi
K
Dept. of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu Univ. School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
Kamijo
Yuji
Y
Hora
Kazuhiko
K
Takahashi
Kyoko
K
Higuchi
Makoto
M
Kiyosawa
Kendo
K
Shigematsu
Hidekazu
H
Gonzalez
Frank J
FJ
Aoyama
Toshifumi
T
D000818:Animals; D002478:Cells, Cultured; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction
D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047493:PPAR alpha