Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 325, Issue 4, Pages F519-F526Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00105.2023
Keywords
diabetes; endothelium; fibrosis; steroids
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This study shows that the absence of endothelial glucocorticoid receptor (GR) leads to accelerated organ fibrosis in a mouse model of diabetes, through upregulation of Wnt signaling. Additionally, the study demonstrates that the fibrosis can be improved with a Wnt inhibitor or metformin. The findings highlight the importance of the synergistic effects of Wnt signaling and inflammation in the pathogenesis of organ fibrosis.
Endothelial cells play a key role in maintaining homeostasis and are deranged in many disease processes, including fibrotic conditions. Absence of the endothelial glucocorticoid receptor (GR) has been shown to accelerate diabetic kidney fibrosis in part through upregulation of Wnt signaling. The db/ db mouse model is a model of spontaneous type 2 diabetes that has been noted to develop fibrosis in multiple organs over time, including the kidneys. This study aimed to determine the effect of loss of endothelial GR on organ fibrosis in the db/db model. db/db mice lacking endothelial GR showed more severe fibrosis in multiple organs compared with endothelial GR-replete db/db mice. Organ fibrosis could be substantially improved either through administration of a Wnt inhibitor or metformin. IL-6 is a key cytokine driving the fibrosis phenotype and is mechanistically linked to Wnt signaling. The db/db model is an important tool to study the mechanisms of fibrosis and its phenotype in the absence of endothelial GR highlights the synergistic effects of Wnt signaling and inflammation in the pathogenesis or organ fibrosis. NEW & NOTEWORTHY The major finding of this work is that endothelial glucocorticoid receptor-mediated upregulation of Wnt signaling and concurrent hyperinflammation work synergistically to exacerbate organ fibrosis in a genetic mouse model of diabetes. This study adds to our understanding of diabetic renal fibrosis and has important implications for the use of metformin in this condition.
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