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Am J Physiol Renal Physiol 296: F328-F336, 2009. First published November 26, 2008; doi:10.1152/ajprenal.00484.2007
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PPAR{alpha} attenuates the proinflammatory response in activated mesangial cells

Keiichi Kono,1,2 Yuji Kamijo,1,2 Kazuhiko Hora,2 Kyoko Takahashi,1,2 Makoto Higuchi,2 Kendo Kiyosawa,2 Hidekazu Shigematsu,3 Frank J. Gonzalez,4 and Toshifumi Aoyama1

1Department of Metabolic Regulation, Institute on Aging and Adaptation, 2Department of Internal Medicine, and 3Department of Pathology, Shinshu University School of Medicine, Matsumoto, Japan; and 4Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland

Submitted 16 October 2007 ; accepted in final form 20 November 2008

The activated mesangial cell is an important therapeutic target for the control of glomerulonephritis. The peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) 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 PPAR{alpha} 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)-{kappa}B signaling pathway. In wild-type cells resistant to inflammation, constitutive expression of PPAR{alpha} was undetectable. However, LPS treatment induced the significant appearance and substantial activation of PPAR{alpha}, which would attenuate the proinflammatory responses through its antagonizing effects on the NF-{kappa}B signaling pathway. The induction of PPAR{alpha} 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 PPAR{alpha}-positive cells in glomeruli, suggesting in vivo correlation with PPAR{alpha} induction. These results suggest that PPAR{alpha} plays crucial roles in the attenuation of inflammatory response in activated mesangial cells. PPAR{alpha} might be a novel therapeutic target against glomerular diseases.

inflammatory response; lipopolysaccharide; nuclear factor-{kappa}B; phenotypic changes; peroxisome proliferator-activated receptor {alpha}


Address for reprint requests and other correspondence: Y. Kamijo, Dept. of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu Univ. School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan (e-mail: yujibeat{at}shinshu-u.ac.jp)






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