TY - JOUR
T1 - The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential
AU - Mori, Hiroyuki
AU - Inoki, Ken
AU - Masutani, Kohsuke
AU - Wakabayashi, Yu
AU - Komai, Kyoko
AU - Nakagawa, Ryusuke
AU - Guan, Kun Liang
AU - Yoshimura, Akihiko
N1 - Funding Information:
We thank T. Yoshioka for her technical assistance. This study was supported by Grants-in-Aid for Scientific Research (S) and for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), and grants from the National Institutes of Health, USA (K.-L.G.).
PY - 2009/7/10
Y1 - 2009/7/10
N2 - 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 hyperinsulinemia 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.
AB - 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 hyperinsulinemia 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.
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U2 - 10.1016/j.bbrc.2009.04.136
DO - 10.1016/j.bbrc.2009.04.136
M3 - Article
C2 - 19422788
AN - SCOPUS:65649120747
SN - 0006-291X
VL - 384
SP - 471
EP - 475
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -
