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ORIGINAL RESEARCH ARTICLE

9HODE Stimulates Cell Proliferation and Extracellular Matrix Synthesis in Human Mesangial Cells via PPAR

Mayumi Negishi^*,1, Hiroyuki Shimizu^*, Shuichi Okada^*, Atsushi Kuwabara, Fumikazu Okajima and Masatomo Mori^*

^* Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashia, Gunma, Japan; Infection Control and Prevention Center of Gunma University Hospital, Maebashi, Gunma, Japan; and Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.

To whom requests for reprints should be addressed at ¹ Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-22 Showamachi, Maebashi, Gunma 371-8511, Japan. E-mail mnegishi{at}med.gunma-u.ac.jp

Plasma oxidized low-density lipoprotein (OX-LDL) levels are elevated in patients with renal diseases, including diabetic nephropathy. We examined effects of OX-LDL on cell proliferation and extracellular matrix (ECM) production by using normal human mesangial cells. Furthermore, we examined possible involvement of peroxisome proliferator-activated receptor gamma (PPAR). Mesangial cell proliferation with OX-LDL, 9-hydroxy-10,12-octadecadienoic acid (9HODE), and 13-hydroxy-9,11-octadecadienoic acid (13HODE), the major components of OX-LDL, were determined by 5-bromo-2'-deoxyuridine (BrdU) or 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) incorporation. The effect of OX-LDL on mesangial cell proliferation with PD98059 pretreatment was determined by BrdU incorporation. Type IV collagen, fibronectin, and PPAR expression with OX-LDL or 9HODE or 13HODE was determined by Western blotting. Type IV collagen expression with antisense oligonucleotide against PPAR pretreatment was also determined by Western blotting. The effect of PD98059 pretreatment on PPAR expression was determined by Western blotting. In mesangial cells exposed to isolated OX-LDL from human plasma, BrdU incorporation was increased, and this increase was deleted by PD98059. Type IV collagen expression was significantly increased by OX-LDL. 9HODE and 13HODE increased BrdU and MTT incorporation into mesangial cells and also increased expressions of Type IV collagen and fibronection, the major components of ECM. PPAR expression in mesangial cells was stimulated by 9HODE. The reduction of PPAR synthesis by pretreatment of antisense oligonucleotide against PPAR remarkably attenuated Type IV collagen synthesis induced by 9HODE. PPAR expression induced by 9HODE was also reduced by PD98059 pretreatment. These findings demonstrate that 9HODE, the major component of OX-LDL, stimulates cell proliferation and ECM production of human mesangial cells. In addition, the stimulatory effects are, at least in part, mediated by PPAR, which may exist in downstream of ERK1/2 pathway. Exp Biol Med 229:1053–1060, 2004.

Key Words: 9HODE • oxidized LDL • mesangial cell • PPAR