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      Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys

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          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.

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          Highlights

          • •

            Endothelial SIRT3 protects against renal fibrosis in diabetes

          • •

            Endothelial SIRT3 regulates mesenchymal metabolic shifts

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            Amelioration of endothelial SIRT3 could be a potential therapeutic approach

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            Targeting defective metabolism offers new therapeutics against kidney diseases

          Abstract

          Biological Sciences ; Cell Biology ; Functional Aspects of Cell Biology

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          Most cited references54

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          Origin and function of myofibroblasts in kidney fibrosis.

          Valerie LeBleu, Gangadhar Taduri, Joyce O'Connell … (2013)
          Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.
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            Role of PFKFB3-driven glycolysis in vessel sprouting.

            Katrien De Bock, Maria Georgiadou, Sandra Schoors … (2013)
            Vessel sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates vessel branching. Copyright © 2013 Elsevier Inc. All rights reserved.
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              BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.

              Michael Zeisberg, Jun-ichi Hanai, Hikaru Sugimoto … (2003)
              Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.
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                Author and article information

                Contributors
                Swayam Prakash Srivastava
                Keizo Kanasaki
                Daisuke Koya
                Journal
                Journal ID (nlm-ta): iScience
                Journal ID (iso-abbrev): iScience
                Title: iScience
                Publisher: Elsevier
                ISSN (Electronic): 2589-0042
                Publication date PMC-release: 06 April 2021
                Publication date Collection: 21 May 2021
                Publication date (Electronic): 06 April 2021
                Volume: 24
                Issue: 5
                Electronic Location Identifier: 102390
                Affiliations
                [1 ]Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
                [2 ]Department of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
                [3 ]Internal Medicine 1, Shimane University, Faculty of Medicine, Izumo, Shimane 693-8501, Japan
                [4 ]Department of Pediatrics (Nephrology) Yale University School of Medicine, New Haven, CT 06520, USA
                [5 ]Vascular Biology and Therapeutics Program, Yale University School of Medicine New Haven, CT 06520, USA
                Author notes
                [∗ ]Corresponding author swayam.cdri@ 123456gmail.com
                [∗∗ ]Corresponding author kkanasak@ 123456med.shimane-u.ac.jp
                [∗∗∗ ]Corresponding author koya0516@ 123456kanazawa-med.ac.jp
                [6]

                Lead contact

                Article
                Publisher Item ID: S2589-0042(21)00358-8 Publisher ID: 102390
                DOI: 10.1016/j.isci.2021.102390
                PMC ID: 8086030
                PubMed ID: 33981977
                SO-VID: a8d8c32d-1d14-40b3-a510-e5e3a0036c15
                Copyright © © 2021 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 7 January 2020
                Date revision received : 23 December 2020
                Date accepted : 31 March 2021
                Categories
                Subject: Article

                Keywords: biological sciences,cell biology,functional aspects of cell biology
                Data availability:
                Keywords: biological sciences, cell biology, functional aspects of cell biology

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