Podocyte Glucocorticoid Receptors Are Essential for Glomerular Endothelial Cell Homeostasis in Diabetes Mellitus

Abstract

Background Proteinuria and glomerular segmental fibrosis are inevitable complications of diabetic nephropathy though their mechanisms are poorly understood. Understanding the clinical characteristics and pathogenesis of proteinuria and glomerular segmental fibrosis in diabetic nephropathy is, therefore, urgently needed for patient management of this severe disease. Methods and Results Diabetes mellitus was induced in podocyte‐specific glucocorticoid receptor knockout (GR PKO ) mice and control littermates by administration of streptozotocin. Primary podocytes were isolated and subjected to analysis of Wnt signaling and fatty acid metabolism. Conditioned media from primary podocytes was transferred to glomerular endothelial cells. Histologic analysis of kidneys from diabetic GR PKO mice showed worsened fibrosis, increased collagen deposition, and glomerulomegaly indicating severe glomerular fibrosis. Higher expression of transforming growth factor‐βR1 and β‐catenin and suppressed expression of carnitine palmitoyltransferase 1A in nephrin‐positive cells were found in the kidneys of diabetic GR PKO mice. Podocytes isolated from diabetic GR PKO mice demonstrated significantly higher profibrotic gene expression and suppressed fatty acid oxidation compared with controls. Administration of a Wnt inhibitor significantly improved the fibrotic features in GR PKO mice. The glomerular endothelium of diabetic GR PKO mice demonstrated the features of endothelial‐to‐mesenchymal transition. Moreover, endothelial cells treated with conditioned media from podocytes lacking GR showed increased expression of α‐smooth muscle actin, transforming growth factor‐βR1 and β‐catenin levels. Conclusions These data demonstrate that loss of podocyte GR leads to upregulation of Wnt signaling and disruption in fatty acid metabolism. Podocyte–endothelial cell crosstalk, mediated through GR, is important for glomerular homeostasis, and its disruption likely contributes to diabetic nephropathy.

Human Liver Stem Cell Derived Extracellular Vesicles Alleviate Kidney Fibrosis by Interfering with the β-Catenin Pathway through miR29b

“…In addition, the involvement of endothelial glucocorticoid receptors in the regulation of the Wnt canonical pathway through the Frzb gene has recently come to light. In particular, the podocyte glucocorticoid receptors were shown to play an essential role in glomerular homeostasis, as their loss contributed towards the activation of the Wnt pathway in diabetic nephropathy [ 13 , 14 ]. There is therefore sufficient evidence to support the involvement of the β-catenin pathway in the progression of kidney fibrosis.…”

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

“…Mechanistically, endothelium derived from podocyte-specific GR knockout mice showed features of endothelial-to-mesenchymal transition. These findings indicate that GR plays an important role in the pathogenesis of DKD by mediating podocyte-endothelial cell crosstalk ( Srivastava et al, 2021a ).…”

“…Deletion of endothelial GR has been shown to accelerate renal fibrosis in diabetic mice by dysregulated cytokine and chemokine reprogramming, augmented Wnt signaling and suppression of fatty acid oxidation ( Srivastava et al, 2021b ). Interestingly, deletion of podocyte GR has been shown to upregulate Wnt signaling and disrupt fatty acid metabolism in diabetic mice, leading to enhanced glomerulosclerosis ( Srivastava et al, 2021a ). Mechanistically, endothelium derived from podocyte-specific GR knockout mice showed features of endothelial-to-mesenchymal transition.…”

Coronavirus Disease (COVID)-19 and Diabetic Kidney Disease

“…However, further studies are required to confirm the therapeutic efficacy of AcSDKP in diabetic COVID-19 endothelium. In addition, podocyte-endothelial crosstalk regulated by glucocorticoid receptors is important for the glomerular health therefore, the search for the new safe non-steroidal GR agonists is needed for development of future generation medication against diabetic nephropathy [154] and such medications could have beneficial effects to COVID-19 patients. Moreover, any medication that supports endothelial cell heath, may be of benefit to diabetic COVID-19 patients.…”