Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys

Srivastava, S. P.; Li, J.; Takagaki, Y.; Kitada, M.; Goodwin, J. E.; Kanasaki, K.; Koya, D.

doi:10.1101/2020.12.15.422824

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bioRxiv · 10.1101/2020.12.15.422824

Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys

Srivastava, S. P.·Li, J.·Takagaki, Y.·Kitada, M.·Goodwin, J. E.·Kanasaki, K.·Koya, D.

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Abstract

Defects in endothelial cells cause deterioration in kidney function and structure. Here, we found that endothelial SIRT3 regulates metabolic reprogramming and fibrogenesis in the kidneys of diabetic mice. By analyzing, gain-of-function of the SIRT3 gene by overexpression in a fibrotic mouse strain conferred disease resistance against diabetic kidney fibrosis; while its loss-of-function in endothelial cells exacerbated the levels of diabetic kidney fibrosis. Regulation of endothelial cell SIRT3 on fibrogenic processes was due to tight control over the defective central metabolism and linked-activation of endothelial-to-mesenchymal transition (EndMT). SIRT3 deficiency in endothelial cells stimulated the TGF{beta}/Smad3-depandent mesenchymal transformations in renal tubular epithelial cells. These data demonstrate that SIRT3 regulates defective metabolism and EndMT-mediated activation of the fibrogenic pathways in the diabetic kidneys. Together, our findings show that endothelial cell SIRT3 is a fundamental regulator of defective metabolism regulating health and disease processes in the kidney. Context and significanceThe present study describes that endothelial cell SIRT3 protects against renal fibrosis by mitigating the metabolic reprogramming and associated mesenchymal transformations in diabetes. Accordingly, amelioration of endothelial cell SIRT3 and targeting the defective metabolism offer a potential therapeutic approach to treat or prevent the progression of diabetic kidney disease. Further investigation would delineate the mechanisms of SIRT3 up-regulation in diabetic kidney disease and discover small molecules to increase the expression of the SIRT3. In addition, this study describes the biology of SIRT3 in the health and disease processes of kidney endothelial cells.

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Srivastava, S. P., Li, J., Takagaki, Y., Kitada, M., Goodwin, J. E., Kanasaki, K., Koya, D.. 2020-12-16. Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys. https://doi.org/10.1101/2020.12.15.422824

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