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

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. In this study, 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 receptor for the advanced glycation end product (RAGE) signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased reactive oxygen species 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.

Qu H ，Gong X ，Liu X ，Zhang R ，Wang Y ，Huang B ，Zhang L ，Zheng H ，Zheng Y ... -  《-》

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy.

Jha JC ，Thallas-Bonke V ，Banal C ，Gray SP ，Chow BS ，Ramm G ，Quaggin SE ，Cooper ME ，Schmidt HH ，Jandeleit-Dahm KA ... -  《-》

Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling.

Liu M ，Liang K ，Zhen J ，Zhou M ，Wang X ，Wang Z ，Wei X ，Zhang Y ，Sun Y ，Zhou Z ，Su H ，Zhang C ，Li N ，Gao C ，Peng J ，Yi F ... -  《Nature Communications》

Podocyte-Specific Loss of Krüppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease.

Mitochondrial injury is uniformly observed in several murine models as well as in individuals with diabetic kidney disease (DKD). Although emerging evidence has highlighted the role of key transcriptional regulators in mitochondrial biogenesis, little is known about the regulation of mitochondrial cytochrome c oxidase assembly in the podocyte under diabetic conditions. We recently reported a critical role of the zinc finger Krüppel-like factor 6 (KLF6) in maintaining mitochondrial function and preventing apoptosis in a proteinuric murine model. In this study, we report that podocyte-specific knockdown of Klf6 increased the susceptibility to streptozotocin-induced DKD in the resistant C57BL/6 mouse strain. We observed that the loss of KLF6 in podocytes reduced the expression of synthesis of cytochrome c oxidase 2 with resultant increased mitochondrial injury, leading to activation of the intrinsic apoptotic pathway under diabetic conditions. Conversely, mitochondrial injury and apoptosis were significantly attenuated with overexpression of KLF6 in cultured human podocytes under hyperglycemic conditions. Finally, we observed a significant reduction in glomerular and podocyte-specific expression of KLF6 in human kidney biopsies with progression of DKD. Collectively, these data suggest that podocyte-specific KLF6 is critical to preventing mitochondrial injury and apoptosis under diabetic conditions.

Horne SJ ，Vasquez JM ，Guo Y ，Ly V ，Piret SE ，Leonardo AR ，Ling J ，Revelo MP ，Bogenhagen D ，Yang VW ，He JC ，Mallipattu SK ... -  《-》

Impaired Podocyte Autophagy Exacerbates Proteinuria in Diabetic Nephropathy.

Tagawa A ，Yasuda M ，Kume S ，Yamahara K ，Nakazawa J ，Chin-Kanasaki M ，Araki H ，Araki S ，Koya D ，Asanuma K ，Kim EH ，Haneda M ，Kajiwara N ，Hayashi K ，Ohashi H ，Ugi S ，Maegawa H ，Uzu T ... -  《-》