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p38 Mitogen-Activated Protein Kinase Contributes to Autoimmune Renal Injury in MRL-Fas^lpr Mice

Yasunori Iwata^*, Takashi Wada^*, Kengo Furuichi^*, Norihiko Sakai^*, Kouji Matsushima, Hitoshi Yokoyama and Ken-ichi Kobayashi^*

*Department of Gastroenterology and Nephrology, Division of Blood Purification, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan; and Department of Molecular Preventive Medicine, University of Tokyo, Tokyo, Japan.

Correspondence to Dr. Takashi Wada, Department of Gastroenterology and Nephrology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8641, Japan. Phone: 81-76-265-2000 ext. 3462; Fax: 81-76-234-4250;

ABSTRACT. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) is responsible for the production and signal transduction of cytokines and chemokines. This study hypothesized that p38 MAPK activation is required for spontaneous autoimmune renal injury in MRL-Fas^lpr mice, resembling human lupus erythematosus. FR167653, a specific inhibitor of p38 MAPK, is orally administrated from 3 or 4 mo of age in MRL-Fas^lpr mice (at doses of 10 or 32mg/kg per day) until 6 mo of age. The phosphorylated p38 MAPK in kidneys of MRL-Fas^lpr mice was evaluated. The number of phosphorylated p38 MAPK-positive cells was increased in diseased kidneys. The daily oral administration of FR167653 decreased p38 MAPK phosphorylation in kidneys, especially in a group of mice administered FR167653 (32 mg/kg per day) daily from 3 to 6 mo of age. FR167653 reduced the accumulation of macrophages and T cell and prevented kidney pathology, resulting in prolonged survival. In addition, FR167653 reduced expression of MCP-1 and TNF- in the diseased kidneys and cultured tubular epithelial cells. Furthermore, FR167653 decreased IgG levels in the diseased kidneys and circulation. These results suggest that the phosphorylation of p38 MAPK is required for the pathogenesis of renal injury in MRL-Fas^lpr mice followed by subsequent expression of renal cytokine/chemokine and IgG production. This study provides evidence that the regulation of p38 MAPK is a novel target for the therapy of renal injury in systemic lupus erythematosus. twada@medf.m.kanazawa-u.ac.jp

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