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Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS.
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; Nikolic-Paterson, David J; Yu, Xueqing.
Affiliation
  • Li J; Shunde Women and Children Hospital, Guangdong Medical University, Shunde, Guangdong, China.
  • Sun YBY; The Second Clinical College, Guangdong Medical University, Dongguan, Guangdong, China.
  • Chen W; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.
  • Fan J; Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.
  • Li S; Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • Qu X; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China.
  • Chen Q; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.
  • Chen R; Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.
  • Zhu D; Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • Zhang J; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China.
  • Wu Z; Biomedical Manufacturing Commonwealth Scientific and Industrial Research Organisation (CSIRO), Melbourne, Vic., Australia.
  • Chi H; Australian Regenerative Medicine Institute, Monash University, Clayton, Vic., Australia.
  • Crawford S; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.
  • Oorschot V; Shunde Women and Children Hospital, Guangdong Medical University, Shunde, Guangdong, China.
  • Puelles VG; Shunde Women and Children Hospital, Guangdong Medical University, Shunde, Guangdong, China.
  • Kerr PG; Shunde Women and Children Hospital, Guangdong Medical University, Shunde, Guangdong, China.
  • Ren Y; Shunde Women and Children Hospital, Guangdong Medical University, Shunde, Guangdong, China.
  • Nilsson SK; The Second Clinical College, Guangdong Medical University, Dongguan, Guangdong, China.
  • Christian M; The Second Clinical College, Guangdong Medical University, Dongguan, Guangdong, China.
  • Tang H; Monash Ramaciotti Cryo EM Platform, Monash Biomedicine Discovery Institute, Clayton, Vic., Australia.
  • Chen W; Monash Ramaciotti Cryo EM Platform, Monash Biomedicine Discovery Institute, Clayton, Vic., Australia.
  • Bertram JF; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.
  • Nikolic-Paterson DJ; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Yu X; Departments of Nephrology and Medicine, Monash Health and Monash University, Clayton, Vic., Australia.
EMBO Rep ; 21(2): e48781, 2020 02 05.
Article in En | MEDLINE | ID: mdl-31916354
Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-ß1/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.
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Full text: 1 Database: MEDLINE Main subject: Diabetes Mellitus / Diabetic Nephropathies / Podocytes Limits: Animals Language: En Year: 2020 Type: Article
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PubMed Links
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Full text: 1 Database: MEDLINE Main subject: Diabetes Mellitus / Diabetic Nephropathies / Podocytes Limits: Animals Language: En Year: 2020 Type: Article