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Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS
Jinhua Li1,2,3,4,5,6, Yu Bo Yang Sun3, Weiyi Chen4
1Shunde Women and Children Hospital, Guangdong Medical University, Shunde, Guangdong, China.
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.
Insights
Smad4 protein plays a key role in diabetic nephropathy (DN) by damaging kidney podocytes. Inhibiting Smad4 in podocytes protects against DN progression, revealing a new mitochondrial mechanism.
Area of Science:
- Nephrology
- Molecular Biology
- Diabetology
Background:
- Diabetic nephropathy (DN) is a primary cause of end-stage kidney disease.
- TGF-β1/Smad3 signaling is implicated in DN pathogenesis, but Smad4's role remains unclear.
Purpose of the Study:
- To investigate the role of Smad4 in podocyte injury during diabetic nephropathy.
- To elucidate the molecular mechanisms by which Smad4 contributes to DN.
Main Methods:
- Utilized anti-Smad4 locked nucleic acid to deplete Smad4 in mouse kidneys.
- Generated conditional Smad4-deleted podocyte mice.
- Analyzed Smad4 localization, mitochondrial function, glycolysis, and protein interactions (PKM2, ATPIF1) in podocytes.
Main Results:
- Smad4 depletion halted podocyte damage and glomerulosclerosis in type 2 DN mice.
- Smad4 was upregulated in human and mouse podocytes during DN.
- Conditional Smad4 deletion in podocytes protected against DN, independent of obesity.
- Hyperglycemia induced Smad4 mitochondrial localization, impairing glycolysis and oxidative phosphorylation, and increasing reactive oxygen species.
- Smad4 directly bound PKM2, reducing its active tetrameric form, and interacted with ATPIF1, decreasing its degradation.
Conclusions:
- Smad4 plays a pathogenic role in diabetic podocyte injury.
- A novel mitochondrial mechanism involving Smad4, PKM2, and ATPIF1 contributes to DN pathogenesis.
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