Glomerular endothelial derived vesicles mediate podocyte dysfunction: A potential role for miRNA

• Published in: PloS one Vol. 15; no. 3; p. e0224852
• Main Authors: Hill, N, Michell, D L, Ramirez-Solano, M, Sheng, Q, Pusey, C, Vickers, K C, Woollard, K J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.03.2020; Public Library of Science (PLoS)
• Subjects: Activation; Biological Transport, Active; Biology and life sciences; Cell adhesion & migration; Cell interactions; Cellular Microenvironment; Communications systems; Criminal investigation; Cytoskeleton; Development and progression; Diseases; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelial growth factors; Endothelium; Extracellular vesicles; Fluorescence; Gene expression; Glomerular Basement Membrane - metabolism; Humans; Inflammatory diseases; Kidney diseases; Kidneys; Medicine; Medicine and Health Sciences; Membrane vesicles; Metabolism; MicroRNA; MicroRNAs - metabolism; miRNA; Mitochondria; Nanoparticles; Permeability; Physical Sciences; Physiological aspects; Podocytes - metabolism; Podocytes - pathology; Research and analysis methods; Secretion; Vascular endothelial growth factor; Vesicles; United Kingdom > UK; United States > US; Tennessee; Nashville Tennessee
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0224852

MicroRNAs (miRNA) are shown to be involved in the progression of several types of kidney diseases. Podocytes maintain the integrity of the glomerular basement membrane. Extracellular vesicles (EV) are important in cell-to-cell communication as they can transfer cellular content between cells, including miRNA. However, little is known about how extracellular signals from the glomerular microenvironment regulate podocyte activity. Using a non-contact transwell system, communication between glomerular endothelial cells (GEnC) and podocytes was characterised in-vitro. Identification of transferred EV-miRNAs from GEnC to podocytes was performed using fluorescence cell tracking and miRNA mimetics. To represent kidney disease, podocyte molecular profiling and functions were analysed after EV treatments derived from steady state or activated GEnC. Our data shows activation of GEnC alters EV-miRNA loading, but activation was not found to alter EV secretion. EV delivery of miRNA to recipient podocytes altered cellular miRNA abundance and effector functions in podocytes, including decreased secretion of VEGF and increased mitochondrial stress which lead to altered cellular metabolism and cytoskeletal rearrangement. Finally, results support our hypothesis that miRNA-200c-3p is transfered by EVs from GEnC to podocytes in response to activation, ultimately leading to podocyte dysfunction.