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

Autor: Julie E. Goodwin, Swayam Prakash Srivastava, Carlos Fernández-Hernando, Ocean Setia, Alan Dardik, Han Zhou
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
medicine.medical_specialty
podocyte
Epithelial-Mesenchymal Transition
Endothelium
endothelium
Nephrology and Kidney
Kidney Glomerulus
030204 cardiovascular system & hematology
Streptozocin
Podocyte
Diabetes Mellitus
Experimental
Diabetic nephropathy
03 medical and health sciences
0302 clinical medicine
Receptors
Glucocorticoid
Fibrosis
Internal medicine
Diabetes mellitus
medicine
glucocorticoid receptor
Animals
Homeostasis
Diabetic Nephropathies
Wnt Signaling Pathway
Cells
Cultured
Original Research
Mice
Knockout
Kidney in Cardiovascular Disease
business.industry
Podocytes
Fatty Acids
Wnt signaling pathway
Endothelial Cells
medicine.disease
Streptozotocin
Wnt signaling
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Animal Models of Human Disease
Gene Expression Regulation
diabetes mellitus
Cardiology and Cardiovascular Medicine
business
medicine.drug
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: 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.
Databáze: OpenAIRE
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