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Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy

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Listed:
  • Swayam Prakash Srivastava

    (Yale University School of Medicine New Haven
    Yale University School of Medicine New Haven
    Kanazawa Medical University)

  • Han Zhou

    (Yale University School of Medicine New Haven
    Yale University School of Medicine New Haven)

  • Ocean Setia

    (Yale University School of Medicine New Haven
    Yale University School of Medicine New Haven)

  • Bing Liu

    (Yale University School of Medicine New Haven
    Yale University School of Medicine New Haven)

  • Keizo Kanasaki

    (Kanazawa Medical University)

  • Daisuke Koya

    (Kanazawa Medical University)

  • Alan Dardik

    (Yale University School of Medicine New Haven
    Yale University School of Medicine New Haven
    VA Connecticut Healthcare System)

  • Carlos Fernandez-Hernando

    (Yale University School of Medicine New Haven
    Yale University School of Medicine New Haven
    Yale University School of Medicine New Haven
    Yale University School of Medicine New Haven)

  • Julie Goodwin

    (Yale University School of Medicine New Haven
    Yale University School of Medicine New Haven)

Abstract

Endothelial cells play a key role in the regulation of disease. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells or neighboring cell types, and in both cases contributes to organ fibrosis. Regulatory control of endothelial cell homeostasis is not well studied. Diabetes accelerates renal fibrosis in mice lacking the endothelial glucocorticoid receptor (GR), compared to control mice. Hypercholesterolemia further enhances severe renal fibrosis. The fibrogenic phenotype in the kidneys of diabetic mice lacking endothelial GR is associated with aberrant cytokine and chemokine reprogramming, augmented Wnt signaling and suppression of fatty acid oxidation. Both neutralization of IL-6 and Wnt inhibition improve kidney fibrosis by mitigating mesenchymal transition. Conditioned media from endothelial cells from diabetic mice lacking endothelial GR stimulate Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic molecule in diabetes.

Suggested Citation

  • Swayam Prakash Srivastava & Han Zhou & Ocean Setia & Bing Liu & Keizo Kanasaki & Daisuke Koya & Alan Dardik & Carlos Fernandez-Hernando & Julie Goodwin, 2021. "Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22617-y
    DOI: 10.1038/s41467-021-22617-y
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