The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential.
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.
Mori
Hiroyuki
H
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Inoki
Ken
K
Masutani
Kohsuke
K
Wakabayashi
Yu
Y
Komai
Kyoko
K
Nakagawa
Ryusuke
R
Guan
Kun-Liang
KL
Yoshimura
Akihiko
A
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000201:enzymology*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000201:enzymology*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D051379:Mice; D008815:Mice, Inbred Strains; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D015183:Restriction Mapping; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000096:biosynthesis; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus