Submitted on October 16, 2007
Accepted on November 20, 2008
PPAR
attenuates the proinflammatory response in activated mesangial cells
Keiichi Kono1, Yuji Kamijo1*, Kazuhiko Hora2, Kyoko Takahashi1, Makoto Higuchi2, Kendo Kiyosawa2, Hidekazu Shigematsu3, Frank J Gonzalez4, and Toshifumi Aoyama5
1 Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano, Japan; Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
2 Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
3 Department of Pathology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
4 Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland, United States
5 Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
* To whom correspondence should be addressed. E-mail: yujibeat{at}shinshu-u.ac.jp.
The activated mesangial cell is an important therapeutic target for the control of glomerulonephritis. The peroxisome proliferator-activated receptor 
(PPAR) 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 in mesangial cells, wild-type and PPAR-null cultured mesangial cells were exposed to LPS. LPS treatment caused enhanced proinflammatory responses in the PPAR-null cells compared to wild-type cells, as revealed by the induction of IL-6, enhanced cell proliferation, and the activation of the NF-
B signaling pathway. In wild-type cells resistant to inflammation, constitutive expression of PPAR was undetectable. However, LPS treatment induced the significant appearance and substantial activation of PPAR, which would attenuate the proinflammatory responses through its antagonizing effects on the NF-B signaling pathway. The induction of PPAR was coincident with the appearance of -smooth muscle actine, which might be associated with the phenotypic changes of mesangial cells. Moreover, another examination using LPS-injected WT mice demonstrated the appearance of PPAR-positive cells in glomeruli, suggesting in vivo correlation with PPAR induction. These results suggest that PPAR plays crucial roles in the attenuation of inflammatory response in activated mesangial cells. PPAR might be a novel therapeutic target against glomerular diseases.
