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Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Reiko Inagi^*, Takanori Kumagai^*, Hiroshi Nishi^*, Takahisa Kawakami^*, Toshio Miyata, Toshiro Fujita^* and Masaomi Nangaku^*

^* Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, and Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan

Correspondence: Dr. Reiko Inagi, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1, Hongo Bunkyo-ku, Tokyo 113-8655, Japan. Phone: +81-3-3815-5411; Fax: +81-3-5800-8806; E-mail: inagi-npr{at}umin.ac.jp

Received for publication July 9, 2007. Accepted for publication November 29, 2007.

Accumulating evidence suggests a pathophysiologic role of endoplasmic reticulum (ER) stress in kidney disease. This study investigated the potential of therapeutic approaches targeting ER stress in the anti-Thy1 model of mesangioproliferative glomerulonephritis in rats. Immunohistochemistry and Western blotting showed a time-dependent increase in the expression of the ER stress–inducible chaperones glucose-regulated protein 78 (GRP78) and oxygen-related protein 150 in isolated glomeruli, especially in the glomerular epithelial cells and mesangial cells, after induction of anti-Thy1 nephritis. For evaluation of whether preconditioning with ER stress ameliorates the severity of disease, rats were pretreated with a subnephritogenic dose of the ER stress inducer tunicamycin or thapsigargin for 4 d before disease was induced. Although preconditioning with ER stress had no effect on the degree of disease induction, it strongly ameliorated the manifestations of disease, evidenced by marked reductions in microaneurysm formation, mesangial proliferation, and adhesion of Bowman's capsule to the glomerular tuft. This improvement in histologic damage was associated with reduced proteinuria (39.4 ± 10.5 versus 126.1 ± 18.1 mg/d; P < 0.01) and with attenuated increases in glucose-regulated protein 78 and oxygen-related protein 150 expression. Of note, pretreatment with tunicamycin or thapsigargin decreased the excessive ER stress–induced intracellular signaling observed in anti-Thy1 nephritis. In conclusion, preconditioning with ER stress ameliorates the severity of disease in rats with anti-Thy1 nephritis. These findings suggest the possibility of therapeutic approaches targeting ER stress in mesangioproliferative glomerulonephritis.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673