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Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease

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posted on 19.03.2021, 18:43 by Hua Qu, Xiaoli Gong, Xiufei Liu, Rui Zhang, Yuren Wang, Bangliang Huang, Linlin Zhang, Hongting Zheng, Yi Zheng
Mitochondrial function is essential for bioenergetics, metabolism and signaling and is compromised in diseases such as proteinuric kidney diseases, contributing to the global burden of kidney failure, cardiovascular morbidity and death. The key cell type that prevents proteinuria is the terminally differentiated glomerular podocyte. Here, we characterized the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated diabetes- or adriamycin-induced proteinuria, podocyte injury and glomerular pathology. RNA sequencing revealed that mGPDH regulated the RAGE signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased ROS generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury significantly improved their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.

Funding

This work was supported by the National Science Fund for Distinguished Young Scholars (No. 81925007), the National Natural Science Foundation of China (No. 82070836, No. 82070881, No. 82000769 and No. 81970752), and the “Talent Project” of Army Medical University (2017R013, 2019R047 and 2019XQYYYJ003-2).

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