The combination of sirolimus and rosiglitazone produces a renoprotective effect on diabetic kidney disease in rats

被引：28

作者：

Flaquer, Maria ^{[3
]}

Lloberas, Nuria ^{[3
]}

Franquesa, Marcella ^{[3
]}

Torras, Joan ^{[1
,3
]}

Vidal, August ^{[2
]}

Luis Rosa, Jose ^{[4
]}

Herrero-Fresneda, Immaculada ^{[3
]}

Grinyo, Josep M. ^{[1
,3
]}

Cruzado, Josep M. ^{[1
,3
]}

机构：

[1] Univ Barcelona, Serv Nephrol, Dept Ciencies Fisiol 2, IDIBELL,Bellvitge Hosp, E-08007 Barcelona, Spain

[2] Univ Barcelona, Bellvitge Hosp, IDIBELL, Pathol Serv, E-08007 Barcelona, Spain

[3] Univ Barcelona, Nephrol Lab, Dept Ciencies Fisiol 2, IDIBELL,Bellvitge Hosp, E-08007 Barcelona, Spain

[4] Univ Barcelona, Dept Ciencies Fisiol 2, IDIBELL, E-08007 Barcelona, Spain

来源：

LIFE SCIENCES | 2010年 / 87卷 / 5-6期

关键词：

Diabetic nephropathy; Rats; Rosiglitazone; Sirolimus; Streptozotocin; ACTIVATED RECEPTOR-GAMMA; PROTEIN PHOSPHATASE 2A; MAMMALIAN TARGET; AGONISTS ATTENUATE; S6; KINASE; NEPHROPATHY; INHIBITION; MTOR; TRANSLATION; PROGRESSION;

D O I：

10.1016/j.lfs.2010.06.004

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Aims: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists and mammalian target of rapamycin (mTOR) inhibitors share mechanisms concerning cell growth and reduction of extracellular matrix accumulation. The purpose of this study was to evaluate the potential synergistic effect of this combination on diabetic kidney disease in rats. Main methods: Diabetes was induced by streptozotocin in 42 male Sprague-Dawley rats. Sixteen weeks after diabetes induction, animals were divided into four groups: diabetic animals without intervention (D), diabetic animals with administration of sirolimus (D + SRL), diabetic animals with administration of rosiglitazone (D + RGT), and diabetic animals with administration of sirolimus and rosiglitazone (D + SRL + RGT). Key findings: At a 30-day follow up, diabetic rats showed higher kidney weight, mean glomerular volume, mesangial expansion and albuminuria compared with non-diabetic rats. mTOR downstream proteins, p-T389-S6K and p-T37/46-4EBP1, were higher in diabetic than non-diabetic kidneys, whereas p-S473-AKT was not, suggesting that hyperglycemia mainly activated the mTORC1 pathway in vivo. Moreover, the catalytic subunit of protein phosphatase 2A (PP2Ac) was down-regulated in the diabetic kidney. Sirolimus inhibited the mTORC1 pathway, while the PPAR-gamma agonist rosiglitazone enhanced PP2Ac and reduced p7056K. Both drugs were associated with a reduction in albuminuria, renal enlargement and mesangial expansion, but without any improvement in glycemic control. Sirolimus and rosiglitazone in combination down-regulated the mTORC1 pathway and over-activated PP2Ac in diabetic kidney. This effect may account for the synergistic reduction of renal hypertrophy, albuminuria and renal TGF-beta 1 observed in diabetic rats treated with SRL + RGT. Significance: The combination of sirolimus and rosiglitazone is renoprotective with respect to diabetic nephropathy. (C) 2010 Elsevier Inc. All rights reserved.

引用

页码：147 / 153

页数：7

共 26 条

[1]

Bak M, 2000, J AM SOC NEPHROL, V11, P1287, DOI 10.1681/ASN.V1171287

[2]

PPAR-α and -γ agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse [J].

Calkin, Anna C. ;

Giunti, Sara ;

Jandeleit-Dahm, Karin A. ;

Allen, Terri J. ;

Cooper, Mark E. ;

Thomas, Merlin C. .

NEPHROLOGY DIALYSIS TRANSPLANTATION, 2006, 21 (09) :2399-2405

[3]

Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition [J].

Cho, Du-Hyong ;

Choi, Yoon Jung ;

Jo, Sangmee Ahn ;

Ryou, Jungsang ;

Kim, Jin Yi ;

Chung, Jongkyeong ;

Jo, Inho .

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2006, 291 (02) :C317-C326

[4]

Cruzado Josep M, 2008, Transplant Rev (Orlando), V22, P73, DOI 10.1016/j.trre.2007.09.003

[5]

mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer [J].

Dann, Stephen G. ;

Selvaraj, Anand ;

Thomas, George .

TRENDS IN MOLECULAR MEDICINE, 2007, 13 (06) :252-259

[6]

Mammalian target of rapamycin inhibition halts the progression of proteinuria in a rat model of reduced renal mass [J].

Diekmann, Fritz ;

Rovira, Jordi ;

Carreras, Joaquim ;

Arellano, Edgar M. ;

Banon-Maneus, Elisenda ;

Ramirez-Bajo, Maria Jose ;

Gutierrez-Dalmau, Alex ;

Brunet, Merce ;

Campistol, Josep M. .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2007, 18 (10) :2653-2660

[7]

Eknoyan G, 2006, J NEPHROL, V19, pS71

[8]

Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome [J].

Guan, YF .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2004, 15 (11) :2801-2815

[9]

Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling [J].

Janssens, V ;

Goris, J .

BIOCHEMICAL JOURNAL, 2001, 353 :417-439

[10]

Peroxisome proliferator-activated receptor-γ and retinoic acid X receptor α represses the TGFβ1 gene via PTEN-mediated p70 ribosomal S6 kinase-1 inhibition:: Role for Zf9 dephosphorylation [J].

Lee, Seung Jin ;

Yang, Eun Kyoung ;

Kim, Sang Geon .

MOLECULAR PHARMACOLOGY, 2006, 70 (01) :415-425

← 1 2 3 →