Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy

Swayam Prakash Srivastava, Han Zhou, Ocean Setia, Bing Liu, Keizo Kanasaki, Daisuke Koya, Alan Dardik, Carlos Fernandez-Hernando and Julie Goodwin ()
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Swayam Prakash Srivastava: Yale University School of Medicine New Haven
Han Zhou: Yale University School of Medicine New Haven
Ocean Setia: Yale University School of Medicine New Haven
Bing Liu: 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
Carlos Fernandez-Hernando: Yale University School of Medicine New Haven
Julie Goodwin: Yale University School of Medicine New Haven

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22617-y

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