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

EMBO Rep. 2020 Feb 5;21(2):e48781. doi: 10.15252/embr.201948781. Epub 2020 Jan 9.

Authors

Jinhua Li^{1

2

3

4

5

6}, Yu Bo Yang Sun³, Weiyi Chen⁴, Jinjin Fan^{5

6}, Songhui Li^{7

8}, Xinli Qu³, Qikang Chen¹, Riling Chen¹, Dajian Zhu¹, Jinfeng Zhang¹, Zhuguo Wu², Honggang Chi², Simon Crawford⁹, Viola Oorschot⁹, Victor G Puelles^{3

10

11}, Peter G Kerr¹¹, Yi Ren¹², Susan K Nilsson^{7

8}, Mark Christian¹³, Huanwen Tang¹⁴, Wei Chen^{5

6}, John F Bertram³, David J Nikolic-Paterson¹¹, Xueqing Yu¹⁵

Affiliations

¹ Shunde Women and Children Hospital, Guangdong Medical University, Shunde, Guangdong, China.
² The Second Clinical College, Guangdong Medical University, Dongguan, Guangdong, China.
³ Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.
⁴ Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.
⁵ Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁶ Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, China.
⁷ Biomedical Manufacturing Commonwealth Scientific and Industrial Research Organisation (CSIRO), Melbourne, Vic., Australia.
⁸ Australian Regenerative Medicine Institute, Monash University, Clayton, Vic., Australia.
⁹ Monash Ramaciotti Cryo EM Platform, Monash Biomedicine Discovery Institute, Clayton, Vic., Australia.
¹⁰ III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹¹ Departments of Nephrology and Medicine, Monash Health and Monash University, Clayton, Vic., Australia.
¹² Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA.
¹³ School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK.
¹⁴ Dongguan Key Laboratory of Environmental Medicine, Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong, China.
¹⁵ Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, 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.

Keywords: ATPIF1; PKM2; Smad4; podocyte; type 2 diabetic nephropathy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus* / metabolism
Diabetic Nephropathies* / genetics
Diabetic Nephropathies* / metabolism
Glycolysis / genetics
Kidney
Mice
Podocytes* / metabolism
Reactive Oxygen Species / metabolism

Substances

Reactive Oxygen Species

Abstract

Publication types

MeSH terms

Substances

Grants and funding