Journal article

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 Show all

EMBO REPORTS | WILEY | Published : 2020

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 ..

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University of Melbourne Researchers

Grants

Awarded by National Health and Medical Research Council of Australia


Awarded by National Natural Science Foundation of China


Awarded by Guangdong Medical University of Provincial and Municipal Construction of Colleges and Universities Project


Awarded by Major Basic Research Project of Guangdong Province, China


Awarded by Guangdong Provincial University Key Platform Featured Innovation Project (Natural Sciences)


Awarded by Provincial Preponderant Key Subjects of Public Health and Preventive Medicine Project


Funding Acknowledgements

This study was supported by the National Health and Medical Research Council of Australia (APP1057581), the National Natural Science Foundation of China (81670667), and Guangdong Medical University of Provincial and Municipal Construction of Colleges and Universities Project (NO. 4SG18001Ga) to J.L; the Major Basic Research Project of Guangdong Province, China (NO. 2017KZDXM041), Guangdong Provincial University Key Platform Featured Innovation Project (Natural Sciences) (NO. 2015KTSCX052), Guangdong Medical University of Provincial and Municipal Construction of Colleges and Universities Project (NO. 4SG18102G and 4SG18056G) and Provincial Preponderant Key Subjects of Public Health and Preventive Medicine Project (NO. 4SG18004G and 4SG17043) to H.T.