SIRT3 deficiency leads to induction of abnormal glycolysis in diabetic kidney with fibrosis

• Published in: Cell death & disease Vol. 9; no. 10; pp. 997 - 14
• Main Authors: Srivastava, Swayam Prakash, Li, Jinpeng, Kitada, Munehiro, Fujita, Hiroki, Yamada, Yuichiro, Goodwin, Julie E., Kanasaki, Keizo, Koya, Daisuke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.09.2018; Springer Nature B.V
• Subjects: 13/21; 13/89; 14/34; 14/63; 45/29; 64/60; 82/51; 96/109; 96/95; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carnitine O-Palmitoyltransferase - metabolism; Cell Biology; Cell Culture; Cell Line; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - chemically induced; Diabetic Nephropathies - pathology; Fibrosis; Gene Knockdown Techniques; Glucose - metabolism; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunology; Kidney - pathology; Kidneys; Life Sciences; Mesenchyme; Mice; Mice, Inbred C57BL; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Phenotypes; Pyruvate Kinase - metabolism; siRNA; Sirtuin 3 - deficiency; Sirtuin 3 - genetics; Sirtuin 3 - metabolism; Smad protein; Streptozocin; Streptozocin - pharmacology; Therapeutic applications; Transfection; Transforming growth factor; Transforming Growth Factor beta2 - metabolism; Transforming growth factor-b
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-1057-0

The regulation of aberrant glucose metabolism in diabetes associated-kidney fibrosis is not well known. In this study we found the suppression of SIRT3 protein level in diabetic kidney, displays responsibility in fibrogenic programming associated with aberrant glycolysis and such abnormal glycolysis is the therapeutic target in diabetes associated-kidney fibrosis. When analyzing different strains of streptozotocin-induced diabetic mice model (fibrotic model: CD-1, less fibrotic model: C57Bl6), we found SIRT3 suppression was associated with kidney fibrosis in fibrotic CD-1; further SIRT3 suppression by systemic administration of SIRT3 siRNA in the diabetic mice, showed profound fibrogenic phenotype in the kidney. Such suppression in SIRT3 was associated with the induction of transforming growth factor-β (TGF-β)/smad signaling, higher level of HIF1α accumulation and PKM2 dimer formation; these alterations subsequently led to abnormal glycolysis and linked abnormal mesenchymal transformations in vivo and in vitro. Inhibition of such aberrant glycolysis suppressed fibrogenic programming and restored SIRT3 level as well. Such aberrant glycolysis was confirmed in the KK/Ta-Ins2Akita mouse, the mouse model of progressive diabetic kidney disease. These data demonstrate that SIRT3 deficiency promotes abnormal glycolysis which is responsible for the fibrogenic pathway in diabetic kidney. Restoration of SIRT3 could be an alternative strategy in combating diabetes associated-kidney fibrosis via inhibition of aberrant glycolysis.