The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential

被引：182

作者：

Mori, Hiroyuki ^{[3
,4
]}

Inoki, Ken ^{[3
]}

Masutani, Kohsuke ^{[4
]}

Wakabayashi, Yu ^{[1
]}

Komai, Kyoko ^{[1
]}

Nakagawa, Ryusuke ^{[1
]}

Guan, Kun-Liang ^{[2
,5
]}

Yoshimura, Akihiko ^{[1
,6
]}

机构：

[1] Keio Univ, Sch Med, Dept Microbiol & Immunol, Shinjyuku Ku, Tokyo 1608582, Japan

[2] Univ Michigan, Inst Life Sci, Inst Gerontol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[4] Kyushu Univ, Dept Med & Clin Sci, Grad Sch Med Sci, Higashi Ku, Fukuoka 8128582, Japan

[5] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA

[6] Japan Sci & Technol JST, CREST, Chiyoda Ku, Tokyo 1020075, Japan

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2009年 / 384卷 / 04期

基金：

美国国家卫生研究院;

关键词：

Nephropathy; Rapamycin; Diabetes; mTOR; S6kinase; CANCER-THERAPY; PREVENTION; TARGET;

D O I：

10.1016/j.bbrc.2009.04.136

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Diabetic nephropathy (DN) associated with type 2 diabetes is the most common cause of end-stage renal disease (ESRD) and a serious health issue in the world. Currently, molecular basis for DN has not been established and only limited clinical treatments are effective in abating the progression to ESRD associated with DN. Here we found that diabetic db/db mice which lack the leptin receptor signaling can be used as a model of ESRD associated with DN. We demonstrated that p70S6-kinase was highly activated in mesangial cells in diabetic obese db/db mice. Furthermore, systemic administration of rapamycin, a specific and potent inhibitor of mTOR, markedly ameliorated pathological changes and renal dysfunctions. Moreover, rapamycin treatment shows a significant reduction in fat deposits and attenuates hyper-insulinemia with few side effects. These results indicate that mTOR activation plays a pivotal role in the development of ESRD and that rapamycin Could be an effective therapeutic agent for DN. (C) 2009 Elsevier Inc. All rights reserved.

引用

页码：471 / 475

页数：5

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