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

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mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. / Inoki, Ken; Mori, Hiroyuki; Wang, Junying; Suzuki, Tsukasa; Hong, SungKi; Yoshida, Sei; Blattner, Simone M; Ikenoue, Tsuneo; Rüegg, Markus A; Hall, Michael N; Kwiatkowski, David J; Rastaldi, Maria P; Huber, Tobias B; Kretzler, Matthias; Holzman, Lawrence B; Wiggins, Roger C; Guan, Kun-Liang.

in: J CLIN INVEST, Jahrgang 121, Nr. 6, 06.2011, S. 2181-96.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Inoki, K, Mori, H, Wang, J, Suzuki, T, Hong, S, Yoshida, S, Blattner, SM, Ikenoue, T, Rüegg, MA, Hall, MN, Kwiatkowski, DJ, Rastaldi, MP, Huber, TB, Kretzler, M, Holzman, LB, Wiggins, RC & Guan, K-L 2011, 'mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice', J CLIN INVEST, Jg. 121, Nr. 6, S. 2181-96. https://doi.org/10.1172/JCI44771

APA

Inoki, K., Mori, H., Wang, J., Suzuki, T., Hong, S., Yoshida, S., Blattner, S. M., Ikenoue, T., Rüegg, M. A., Hall, M. N., Kwiatkowski, D. J., Rastaldi, M. P., Huber, T. B., Kretzler, M., Holzman, L. B., Wiggins, R. C., & Guan, K-L. (2011). mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J CLIN INVEST, 121(6), 2181-96. https://doi.org/10.1172/JCI44771

Vancouver

Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J CLIN INVEST. 2011 Jun;121(6):2181-96. https://doi.org/10.1172/JCI44771

Bibtex

@article{56d4f541771b488a9e0d9c53a884392c,
title = "mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice",
abstract = "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 mislocalization 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.",
keywords = "Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Differentiation, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Disease Models, Animal, Endoplasmic Reticulum, Enzyme Activation, Glomerular Basement Membrane, Glomerular Mesangium, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Multiprotein Complexes, Phosphorylation, Podocytes, Protein Processing, Post-Translational, Proteins, Ribosomal Protein S6 Kinases, Sirolimus, TOR Serine-Threonine Kinases, Tumor Suppressor Proteins, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",
author = "Ken Inoki and Hiroyuki Mori and Junying Wang and Tsukasa Suzuki and SungKi Hong and Sei Yoshida and Blattner, {Simone M} and Tsuneo Ikenoue and R{\"u}egg, {Markus A} and Hall, {Michael N} and Kwiatkowski, {David J} and Rastaldi, {Maria P} and Huber, {Tobias B} and Matthias Kretzler and Holzman, {Lawrence B} and Wiggins, {Roger C} and Kun-Liang Guan",
year = "2011",
month = jun,
doi = "10.1172/JCI44771",
language = "English",
volume = "121",
pages = "2181--96",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",

}

RIS

TY - JOUR

T1 - mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice

AU - Inoki, Ken

AU - Mori, Hiroyuki

AU - Wang, Junying

AU - Suzuki, Tsukasa

AU - Hong, SungKi

AU - Yoshida, Sei

AU - Blattner, Simone M

AU - Ikenoue, Tsuneo

AU - Rüegg, Markus A

AU - Hall, Michael N

AU - Kwiatkowski, David J

AU - Rastaldi, Maria P

AU - Huber, Tobias B

AU - Kretzler, Matthias

AU - Holzman, Lawrence B

AU - Wiggins, Roger C

AU - Guan, Kun-Liang

PY - 2011/6

Y1 - 2011/6

N2 - 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 mislocalization 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.

AB - 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 mislocalization 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.

KW - Adaptor Proteins, Signal Transducing

KW - Animals

KW - Carrier Proteins

KW - Cell Differentiation

KW - Diabetes Mellitus, Type 2

KW - Diabetic Nephropathies

KW - Disease Models, Animal

KW - Endoplasmic Reticulum

KW - Enzyme Activation

KW - Glomerular Basement Membrane

KW - Glomerular Mesangium

KW - Male

KW - Membrane Proteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mice, Mutant Strains

KW - Multiprotein Complexes

KW - Phosphorylation

KW - Podocytes

KW - Protein Processing, Post-Translational

KW - Proteins

KW - Ribosomal Protein S6 Kinases

KW - Sirolimus

KW - TOR Serine-Threonine Kinases

KW - Tumor Suppressor Proteins

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1172/JCI44771

DO - 10.1172/JCI44771

M3 - SCORING: Journal article

C2 - 21606597

VL - 121

SP - 2181

EP - 2196

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 6

ER -