Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys
Swayam Prakash Srivastava,
Jinpeng Li,
Yuta Takagaki,
Munehiro Kitada,
Julie E. Goodwin,
Keizo Kanasaki,
Daisuke Koya
Affiliations
Swayam Prakash Srivastava
Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Department of Pediatrics (Nephrology) Yale University School of Medicine, New Haven, CT 06520, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine New Haven, CT 06520, USA; Corresponding author
Jinpeng Li
Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
Yuta Takagaki
Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
Munehiro Kitada
Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Department of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
Julie E. Goodwin
Department of Pediatrics (Nephrology) Yale University School of Medicine, New Haven, CT 06520, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine New Haven, CT 06520, USA
Keizo Kanasaki
Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Department of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Internal Medicine 1, Shimane University, Faculty of Medicine, Izumo, Shimane 693-8501, Japan; Corresponding author
Daisuke Koya
Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Department of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Corresponding author
Summary: 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, whereas 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 TGFβ/Smad3-dependent 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 SIRT3 is a fundamental regulator of defective metabolism regulating health and disease processes in the kidney.
