Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy

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.

TGF-Beta as a Master Regulator of Diabetic Nephropathy

“…Interestingly, the glucocorticoid receptor (GR) signaling also plays a protective role in DN. A recent study showed that endothelial deletion of GR accelerates fibrosis in DN by enhancing EndoMT [147]. Mechanistically, GR suppresses TGF-β/Smad3 signaling by physically interacting with Smad3 protein and inhibiting its activity [148].…”

“…Therefore, GR may serve as an inhibitor of Smad3. However, the GR agonist dexamethasone shows unfavorable side effects to exacerbate hyperglycemia [147].…”

Interactions among Long Non-Coding RNAs and microRNAs Influence Disease Phenotype in Diabetes and Diabetic Kidney Disease

“…Pathological stimuli such as inflammation, diabetes and ageing influence EndMT events in the kidneys [ 69 ]. Endothelial SIRT3, the nuclear receptor glucocorticoid receptor (GR) and cell surface FGFR1 are critical regulators of TGFβ signaling and EndMT in diabetic kidneys [ 70 , 71 , 72 , 73 ]. The kidneys of diabetic mice showed both progressive glomerular sclerosis and tubulointerstitial fibrosis, which was associated with approximately 40% of all FSP-1-positive cells and 50% of αSMA-positive stromal cells were CD31-positive [ 74 ].…”

Editorial: Combating Diabetes and Diabetic Kidney Disease

“…Glucocorticoid receptors (GR) are essential for endothelial cell homeostasis and regulate defective metabolism in endothelial cells. Endothelial GR regulates renal fibrogenesis by targeting Wnt signaling, defective fatty acid oxidation and associated mesenchymal activation in diabetic kidneys (Srivastava et al, 2021b). In this issue, the authors discuss new cellular mechanisms and cell signaling in the regulation of DKD pathogenesis.…”