mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice

被引：540

作者：

Inoki, Ken ^{[1
,2
,3
]}

Mori, Hiroyuki ^{[2
]}

Wang, Junying ^{[1
]}

Suzuki, Tsukasa ^{[1
]}

Hong, SungKi ^{[1
]}

Yoshida, Sei ^{[1
]}

Blattner, Simone M. ^{[3
]}

Ikenoue, Tsuneo ^{[1
]}

Rueegg, Markus A. ^{[4
]}

Hall, Michael N. ^{[4
]}

Kwiatkowski, David J. ^{[5
]}

Rastaldi, Maria P. ^{[6
,7
]}

Huber, Tobias B. ^{[8
,9
]}

Kretzler, Matthias ^{[3
]}

Holzman, Lawrence B. ^{[10
]}

Wiggins, Roger C. ^{[3
]}

Guan, Kun-Liang ^{[11
]}

机构：

[1] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA

[4] Univ Basel, Biozentrum, Basel, Switzerland

[5] Harvard Univ, Brigham & Womens Hosp, Sch Med, Translat Med Div,Dept Med, Boston, MA 02115 USA

[6] Fdn IRCCS Policlin, Renal Res Lab, Milan, Italy

[7] Fdn Amico, Milan, Italy

[8] Univ Hosp Freiburg, Div Renal, Freiburg, Germany

[9] Univ Freiburg, Ctr Biol Signalling Studies Bioss, Freiburg, Germany

[10] Univ Penn, Sch Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA

[11] Univ Calif San Diego, Moores Canc Ctr, Dept Pharmacol, San Diego, CA USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2011年 / 121卷 / 06期

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; TUBEROUS-SCLEROSIS; NEPHRIN EXPRESSION; GLOMERULAR PROTEIN; MAMMALIAN TARGET; KIDNEY-DISEASE; SLIT DIAPHRAGM; ANGIOTENSIN-II; NOTCH PATHWAY; ER STRESS;

D O I：

10.1172/JCI44771

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1 activation induced by ablation of an upstream negative regulator (PcKOTsc1) recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic young and adult mice. Abnormal mTORC1 activation caused mislocalizadon of slit diaphragm proteins and induced an epithelial-mesenchymal transition-like phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of ER stress with a chemical chaperone significantly protected against both the podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic reduction of podocyte-specific mTORC1 in diabetic animals suppressed the development of DN. These results indicate that mTORC1 activation in podocytes is a critical event in inducing DN and suggest that reduction of podocyte mTORC1 activity is a potential therapeutic strategy to prevent DN.

引用

页码：2181 / 2196

页数：16

共 74 条

[1] Nephrin and Neph1 co-localize at the podocyte foot process intercellular junction and form cis hetero-oligomers [J].