Rapamycin prevents early steps of the development of diabetic nephropathy in rats.
OBJECTIVE
Recent studies suggested the involvement of the Akt/mammalian target of rapamycin (mTOR) pathway in the pathogenesis of diabetic nephropathy. The effect of mTOR blockade by rapamycin in diabetic nephropathy was investigated, but in vivo study of rapamycin treatment in the course of early diabetes is still insufficient. This study was designed to determine the therapeutic effects of rapamycin on diabetic nephropathy at an early stage.


METHODS
Diabetes was induced in Sprague-Dawley rats with streptozotocin, and rapamycin (1 mg/kg) was administered by daily gavage for 4 weeks. Renal structural changes and some factors involved in the early pathogenesis of diabetic nephropathy were tested. The activation level of the Akt/mTOR pathway was also determined.


RESULTS
Rapamycin treatment reduced albuminuria, glomerular enlargement, glomerular basement membrane thickening, renal macrophage recruitment, and levels of renal mRNA expression of proliferating cell nuclear antigen, transforming growth factor-beta1, vascular endothelial growth factor, and monocyte chemoattractant protein-1 without change in blood glucose level and blood pressure in experimental diabetic rats. In addition, treatment with rapamycin also down-regulated the enhanced levels of renal p-Akt, phospho-p70S6 kinase, and phospho-ribosomal S6 protein in diabetic rats.


CONCLUSIONS
Rapamycin treatment can prevent the early renal structural changes of diabetes in experimental rats, and thus halt the early steps of the development of diabetic nephropathy. mTOR blockade might be beneficial for the treatment of diabetic nephropathy.
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Yi
Y
Yang
Jingjing
J
Wang
Ling
L
Qin
Zhangfei
Z
Shou
Jie
J
Zhao
Huiping
H
Wang
Ying
Y
Chen
Jianghua
J
Chen
D000419:Albuminuria / Q000503:physiopathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000652:urine; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D050533:Glomerular Basement Membrane / Q000187:drug effects / Q000473:pathology; D006984:Hypertrophy; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008297:Male; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D000893:Anti-Inflammatory Agents; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus