Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS

Jinhua Li; Yu Bo Yang Sun; Weiyi Chen; Jinjin Fan; Songhui Li; Xinli Qu; Qikang Chen; Riling Chen; Dajian Zhu; Jinfeng Zhang; Zhuguo Wu; Honggang Chi; Simon Crawford; Viola Oorschot; Victor G. Puelles; Peter G. Kerr; Yi Ren; Susan K. Nilsson; Mark Christian; Huanwen Tang; Wei Chen; John F. Bertram; David J. Nikolic-Paterson; Xueqing Yu

doi:10.15252/embr.201948781

Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS

Jinhua Li, Yu Bo Yang Sun, Weiyi Chen, Jinjin Fan, Songhui Li, Xinli Qu, Qikang Chen, Riling Chen, Dajian Zhu, Jinfeng Zhang, Zhuguo Wu, Honggang Chi, Simon Crawford, Viola Oorschot, Victor G. Puelles, Peter G. Kerr, Yi Ren, Susan K. Nilsson, Mark Christian, Huanwen TangWei Chen, John F. Bertram, David J. Nikolic-Paterson, Xueqing Yu

Research output: Contribution to journal › Article › Research › peer-review

47 Citations (Scopus)

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-β1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Smad4 depletion in the kidney using anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. Smad4 is upregulated in human and mouse podocytes during DN. Conditional Smad4 deletion in podocytes protects mice from type 2 DN, independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localization to mitochondria in podocytes, resulting in reduced glycolysis and oxidative phosphorylation and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 and reducing the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.

Original language	English
Article number	e48781
Number of pages	20
Journal	EMBO Reports
Volume	21
Issue number	2
DOIs	https://doi.org/10.15252/embr.201948781
Publication status	Published - 5 Feb 2020

Keywords

ATPIF1
PKM2
podocyte
Smad4
type 2 diabetic nephropathy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.15252/embr.201948781

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Li, J., Sun, Y. B. Y., Chen, W., Fan, J., Li, S., Qu, X., Chen, Q., Chen, R., Zhu, D., Zhang, J., Wu, Z., Chi, H., Crawford, S., Oorschot, V., Puelles, V. G., Kerr, P. G., Ren, Y., Nilsson, S. K., Christian, M., ... Yu, X. (2020). Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS. EMBO Reports, 21(2), Article e48781. https://doi.org/10.15252/embr.201948781

@article{97efafdfd6954069a8c1ebd30ca60ec3,

title = "Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS",

abstract = "Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-β1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Smad4 depletion in the kidney using anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. Smad4 is upregulated in human and mouse podocytes during DN. Conditional Smad4 deletion in podocytes protects mice from type 2 DN, independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localization to mitochondria in podocytes, resulting in reduced glycolysis and oxidative phosphorylation and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 and reducing the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.",

keywords = "ATPIF1, PKM2, podocyte, Smad4, type 2 diabetic nephropathy",

author = "Jinhua Li and Sun, {Yu Bo Yang} and Weiyi Chen and Jinjin Fan and Songhui Li and Xinli Qu and Qikang Chen and Riling Chen and Dajian Zhu and Jinfeng Zhang and Zhuguo Wu and Honggang Chi and Simon Crawford and Viola Oorschot and Puelles, {Victor G.} and Kerr, {Peter G.} and Yi Ren and Nilsson, {Susan K.} and Mark Christian and Huanwen Tang and Wei Chen and Bertram, {John F.} and Nikolic-Paterson, {David J.} and Xueqing Yu",

year = "2020",

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doi = "10.15252/embr.201948781",

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Li, J, Sun, YBY, Chen, W, Fan, J, Li, S, Qu, X, Chen, Q, Chen, R, Zhu, D, Zhang, J, Wu, Z, Chi, H, Crawford, S, Oorschot, V, Puelles, VG, Kerr, PG, Ren, Y, Nilsson, SK, Christian, M, Tang, H, Chen, W, Bertram, JF , Nikolic-Paterson, DJ & Yu, X 2020, 'Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS', EMBO Reports, vol. 21, no. 2, e48781. https://doi.org/10.15252/embr.201948781

TY - JOUR

T1 - Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS

AU - Li, Jinhua

AU - Sun, Yu Bo Yang

AU - Chen, Weiyi

AU - Fan, Jinjin

AU - Li, Songhui

AU - Qu, Xinli

AU - Chen, Qikang

AU - Chen, Riling

AU - Zhu, Dajian

AU - Zhang, Jinfeng

AU - Wu, Zhuguo

AU - Chi, Honggang

AU - Crawford, Simon

AU - Oorschot, Viola

AU - Puelles, Victor G.

AU - Kerr, Peter G.

AU - Ren, Yi

AU - Nilsson, Susan K.

AU - Christian, Mark

AU - Tang, Huanwen

AU - Chen, Wei

AU - Bertram, John F.

AU - Nikolic-Paterson, David J.

AU - Yu, Xueqing

PY - 2020/2/5

Y1 - 2020/2/5

N2 - Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-β1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Smad4 depletion in the kidney using anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. Smad4 is upregulated in human and mouse podocytes during DN. Conditional Smad4 deletion in podocytes protects mice from type 2 DN, independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localization to mitochondria in podocytes, resulting in reduced glycolysis and oxidative phosphorylation and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 and reducing the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.

AB - Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-β1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Smad4 depletion in the kidney using anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. Smad4 is upregulated in human and mouse podocytes during DN. Conditional Smad4 deletion in podocytes protects mice from type 2 DN, independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localization to mitochondria in podocytes, resulting in reduced glycolysis and oxidative phosphorylation and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 and reducing the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.

KW - ATPIF1

KW - PKM2

KW - podocyte

KW - Smad4

KW - type 2 diabetic nephropathy

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U2 - 10.15252/embr.201948781

DO - 10.15252/embr.201948781

M3 - Article

C2 - 31916354

AN - SCOPUS:85077866176

SN - 1469-221X

VL - 21

JO - EMBO Reports

JF - EMBO Reports

IS - 2

M1 - e48781

ER -

Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS

Abstract

Keywords

UN SDGs

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Smad3 acetylation modulates organ fibrosis

Ramaciotti Centre for Cryo-Electron Microscopy

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Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

Smad3 acetylation modulates organ fibrosis

Equipment

Ramaciotti Centre for Cryo-Electron Microscopy

Cite this