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

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-beta R1 and beta-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 alpha-smooth muscle actin, transforming growth factor-beta R1 and beta-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.

Automated summary

The study found that the loss of glucocorticoid receptor in podocytes leads to upregulation of the Wnt signaling pathway and disruption in fatty acid metabolism, resulting in the development of diabetic nephropathy. The crosstalk between podocytes and endothelial cells is crucial for maintaining glomerular homeostasis, and its disruption may contribute to diabetic nephropathy.