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Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS
Author(s) -
Li Jinhua,
Sun Yu Bo Yang,
Chen Weiyi,
Fan Jinjin,
Li Songhui,
Qu Xinli,
Chen Qikang,
Chen Riling,
Zhu Dajian,
Zhang Jinfeng,
Wu Zhuguo,
Chi Honggang,
Crawford Simon,
Oorschot Viola,
Puelles Victor G,
Kerr Peter G,
Ren Yi,
Nilsson Susan K,
Christian Mark,
Tang Huanwen,
Chen Wei,
Bertram John F,
NikolicPaterson David J,
Yu Xueqing
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948781
Subject(s) - podocyte , oxidative phosphorylation , diabetic nephropathy , glomerulosclerosis , glycolysis , microbiology and biotechnology , downregulation and upregulation , reactive oxygen species , mitochondrion , biology , focal segmental glomerulosclerosis , kidney , cancer research , chemistry , endocrinology , biochemistry , glomerulonephritis , metabolism , proteinuria , gene
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 PKM 2 and reducing the active tetrameric form of PKM 2. In addition, Smad4 interacts with ATPIF 1, causing a reduction in ATPIF 1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.