title: Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats.
abstract: Recent data suggest that the phosphatidylinositol 3-kinase (PI3-K)/Akt/mammalian target of rapamycin (mTOR) pathway is important in diabetic nephropathy. The effect of mTOR blockade by sirolimus (SRL) in diabetic kidney disease in rats was investigated. Diabetes was induced by streptozotocin in male Sprague-Dawley rats. Sixteen weeks later, diabetic animals were divided into the following groups: diabetes (D; n = 8), diabetes + SRL at 1 mg/kg per d, SRL trough level 2.3 +/- 0.25 ng/ml (D+SRL; n = 7); and diabetes + normoglycemia maintained by insulin implants (D+NG; n = 5). There was an age-matched nondiabetic group (ND; n = 6). All animals were followed for 4 wk. The D group showed glomerular hypertrophy (mean glomerular volume 5.0 +/- 0.4 in D versus 3.3 +/- 0.2 10(6) mu(3) in ND; P < 0.05) without renal hyperplasia (calculated by reverse transcription-PCR of proliferative cell nuclear antigen) and albuminuria (29 +/- 4 in D versus 1.4 +/- 1.5 mg/24 h in ND; P < 0.05). Both D+NG and D+SRL groups had a significant reduction of albuminuria, although glomerular hypertrophy was still present. SRL treatment did not modify the number of infiltrating renal ED1(+) cells. Diabetic animals had greater expression of p-Akt and mTOR, unlike ND rats. NG and SRL treatment reduced p-Akt and normalized mTOR. It is interesting that D+SRL was associated with a significant reduction of renal TGF-beta1 and glomerular connective tissue growth factor. SRL treatment reduced glomerular alpha-smooth muscle actin overexpression and reduced significantly the mesangial matrix accumulation that is characteristic of diabetic nephropathy. In conclusion, mTOR blockade by low-dose SRL has a beneficial effect in diabetic kidney disease, suggesting that the mTOR pathway has an important pathogenic role in diabetic nephropathy.
authors.affiliation: Nephrology Service, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Lloberas
authors.forename: Josep M
authors.initials: JM
authors.lastname: Cruzado
authors.forename: Marcella
authors.initials: M
authors.lastname: Franquesa
authors.forename: Immaculada
authors.initials: I
authors.lastname: Herrero-Fresneda
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alperovich
authors.forename: Inés
authors.initials: I
authors.lastname: Rama
authors.forename: August
authors.initials: A
authors.lastname: Vidal
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control*; D018450:Disease Progression; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D013311:Streptozocin; D058570:TOR Serine-Threonine Kinases
chemical_list: D007166:Immunosuppressive Agents; D013311:Streptozocin; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus