Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats. Export

@article{citeulike:1434429, 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.}, address = {Nephrology Service, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Catalonia, Spain.}, author = {Lloberas, N\'{u}ria and Cruzado, Josep M. and Franquesa, Marcella and Herrero-Fresneda, Immaculada and Torras, Joan and Alperovich, Gabriela and Rama, In\'{e}s and Vidal, August and Griny\'{o}, Josep M.}, citeulike-article-id = {1434429}, citeulike-linkout-0 = {http://dx.doi.org/10.1681/ASN.2005050549}, citeulike-linkout-1 = {http://jasn.asnjournals.org/cgi/content/abstract/17/5/1395}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16597691}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16597691}, day = {1}, doi = {10.1681/ASN.2005050549}, issn = {1046-6673}, journal = {Journal of the American Society of Nephrology : JASN}, keywords = {1, dn, mtor, rat, stz}, month = {May}, number = {5}, pages = {1395--1404}, posted-at = {2007-07-05 03:34:12}, priority = {2}, title = {Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats.}, url = {http://dx.doi.org/10.1681/ASN.2005050549}, volume = {17}, year = {2006} }

TY - JOUR ID - citeulike:1434429 L3 - citeulike-article-id:1434429 N2 - 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. IS - 5 JF - Journal of the American Society of Nephrology : JASN SN - 1046-6673 AD - Nephrology Service, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Catalonia, Spain. EP - 1404 TI - Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats. VL - 17 SP - 1395 KW - 1 KW - dn KW - mtor KW - rat KW - stz AU - Lloberas, Núria AU - Cruzado, Josep AU - Franquesa, Marcella AU - Herrero-Fresneda, Immaculada AU - Torras, Joan AU - Alperovich, Gabriela AU - Rama, Inés AU - Vidal, August AU - Grinyó, Josep PY - 2006/05/01/ UR - http://dx.doi.org/10.1681/ASN.2005050549 ER -