Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS

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. ORCID: 0000-0002-1616-4179, Tang, H., Chen, W., Bertram, J.F., Nikolic‐Paterson, D.J. and Yu, X., 2020. Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS. EMBO Reports, 21 (2): e48781. ISSN 1469-221X

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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.

Item Type: Journal article
Alternative Title: Smad4 in diabetic nephropathy [running head]
Publication Title: EMBO Reports
Creators: 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., Tang, H., Chen, W., Bertram, J.F., Nikolic‐Paterson, D.J. and Yu, X.
Publisher: EMBO Press
Date: 5 February 2020
Volume: 21
Number: 2
ISSN: 1469-221X
Identifiers:
NumberType
10.15252/embr.201948781DOI
1267858Other
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 20 Jan 2020 16:12
Last Modified: 18 Feb 2020 12:22
URI: http://irep.ntu.ac.uk/id/eprint/39017

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