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Am J Physiol Renal Physiol 297: F679-F684, 2009. First published July 1, 2009; doi:10.1152/ajprenal.90680.2008
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Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice

Mari Tomiyama-Hanayama,1 Hiromi Rakugi,1 Masaharu Kohara,3 Toru Mima,2 Yasuo Adachi,2 Mitsuru Ohishi,1 Tomohiro Katsuya,1 Yoshihiko Hoshida,3 Katsuyuki Aozasa,3 Toshio Ogihara,1 and Norihiro Nishimoto2

1Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka; 2Laboratory of Immune Regulation, Wakayama Medical University, Wakayama; and 3Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan

Submitted 14 November 2008 ; accepted in final form 25 June 2009

Hyperlipidemia has been demonstrated to be associated with renal disease, yet the mechanism of renal injury is still poorly understood. Inflammation that occurs with the hyperlipidemia has been considered to play an important role in development of glomerular injury. In the present study, we investigated the role of interleukin-6 (IL-6), a key inflammatory molecule, on renal injury in apolipoprotein E-deficient (ApoE–/–) mice with severe hypercholesterolemia. The 6-wk-old mice were fed a high-fat diet and administered weekly rat anti-IL-6 receptor monoclonal antibody (MR16-1), control rat IgG, or saline for a total of 4 wk. We examined histopathological changes in the kidney and urinary excretion of protein and albumin. Saline- and IgG-treated mice showed remarkable proteinuria at 10 wk of age, whereas MR16-1-treated mice exhibited significantly lower levels. Renal histopathology of saline- and IgG-treated mice revealed striking lipid deposits and foam cells in the glomerular tuft, juxtaglomerular area, and arteriolar wall along with range of mesangial cell proliferation and matrix expansion. Notably, the severity of lipid deposits and mesangial cell proliferation were significantly reduced in MR16-1-treated mice. Immunohistochemistry demonstrated that mesangial IL-6 expression was dramatically reduced in MR16-1-treated mice compared with IgG-treated mice. Blocking the IL-6 receptor prevented progression of proteinuria and renal lipid deposit, as well as the mesangial cell proliferation associated with severe hyperlipoproteinemia. These results clearly demonstrate that IL-6 plays an essential role in the pathogenesis of hyperlipidemia-induced glomerular injury in ApoE–/– mice and suggests the usefulness of anti-IL-6 receptor antibody in treatments for hyperlipidemia-induced organ damage.

mesangial cells; macrophages; anti-mouse interleukin-6 receptor antibody MR16-1


Address for reprint requests and other correspondence: N. Nishimoto, Laboratory of Immune Regulation, Wakayama Medical Univ., 105 Saito Bio Innovation Center, 7-7-20, Saito-Asagi, Ibaraki-city, Osaka 567-0085, Japan (e-mail: norichan{at}wakayama-med.ac.jp)






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