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.
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Hiroyuki
H
Mori
Ken
K
Inoki
Kohsuke
K
Masutani
Yu
Y
Wakabayashi
Kyoko
K
Komai
Ryusuke
R
Nakagawa
Kun-Liang
KL
Guan
Akihiko
A
Yoshimura
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