Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy.
Adrenalectomy
Animals
Diabetes Mellitus, Experimental
/ blood
Diabetic Nephropathies
/ blood
Endothelial Cells
/ pathology
Endothelium
/ cytology
Epithelial-Mesenchymal Transition
/ drug effects
Fatty Acids
/ metabolism
Fibrosis
Glucocorticoids
/ metabolism
Humans
Hypercholesterolemia
/ blood
Interleukin-6
/ antagonists & inhibitors
Kidney Tubules
/ cytology
Male
Mice
Mice, Knockout, ApoE
Oxidation-Reduction
Receptors, Glucocorticoid
/ deficiency
Streptozocin
/ administration & dosage
Wnt Signaling Pathway
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 04 2021
22 04 2021
Historique:
received:
18
02
2020
accepted:
23
03
2021
entrez:
23
4
2021
pubmed:
24
4
2021
medline:
12
5
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33888696
doi: 10.1038/s41467-021-22617-y
pii: 10.1038/s41467-021-22617-y
pmc: PMC8062600
doi:
Substances chimiques
Fatty Acids
0
Glucocorticoids
0
Interleukin-6
0
Receptors, Glucocorticoid
0
interleukin-6, mouse
0
Streptozocin
5W494URQ81
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2368Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL131952
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135820
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128406
Pays : United States
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