PUBLICATION
Glomerular Endothelial Cell-Derived miR-200c Impairs Glomerular Homeostasis by Targeting Podocyte VEGF-A
- Authors
- Ursu, R., Sopel, N., Ohs, A., Tati, R., Buvall, L., Nyström, J., Schiffer, M., Müller-Deile, J.
- ID
- ZDB-PUB-221212-7
- Date
- 2022
- Source
- International Journal of Molecular Sciences 23(23): (Journal)
- Registered Authors
- Keywords
- VEGF-A, endotheliosis, glomerulus, miR-200c, podocytopathies, proteinuria, zebrafish
- MeSH Terms
-
- Animals
- Endothelial Cells*/metabolism
- Epithelial-Mesenchymal Transition
- Humans
- MicroRNAs*/genetics
- MicroRNAs*/metabolism
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 36499397 Full text @ Int. J. Mol. Sci.
Citation
Ursu, R., Sopel, N., Ohs, A., Tati, R., Buvall, L., Nyström, J., Schiffer, M., Müller-Deile, J. (2022) Glomerular Endothelial Cell-Derived miR-200c Impairs Glomerular Homeostasis by Targeting Podocyte VEGF-A. International Journal of Molecular Sciences. 23(23):.
Abstract
Deciphering the pathophysiological mechanisms of primary podocytopathies that can lead to end-stage renal disease and increased mortality is an unmet need. Studying how microRNAs (miRs) interfere with various signaling pathways enables identification of pathomechanisms, novel biomarkers and potential therapeutic options. We investigated the expression of miR-200c in urine from patients with different renal diseases as a potential candidate involved in podocytopathies. The role of miR-200c for the glomerulus and its potential targets were studied in cultured human podocytes, human glomerular endothelial cells and in the zebrafish model. miR-200c was upregulated in urine from patients with minimal change disease, membranous glomerulonephritis and focal segmental glomerulosclerosis and also in transforming growth factor beta (TGF-β) stressed glomerular endothelial cells, but not in podocytes. In zebrafish, miR-200c overexpression caused proteinuria, edema, podocyte foot process effacement and glomerular endotheliosis. Although zinc finger E-Box binding homeobox 1/2 (ZEB1/2), important in epithelial to mesenchymal transition (EMT), are prominent targets of miR-200c, their downregulation did not explain our zebrafish phenotype. We detected decreased vegfaa/bb in zebrafish overexpressing miR-200c and could further prove that miR-200c decreased VEGF-A expression and secretion in cultured human podocytes. We hypothesize that miR-200c is released from glomerular endothelial cells during cell stress and acts in a paracrine, autocrine, as well as context-dependent manner in the glomerulus. MiR-200c can cause glomerular damage most likely due to the reduction of podocyte VEGF-A. In contrast, miR-200c might also influence ZEB expression and therefore EMT, which might be important in other conditions. Therefore, we propose that miR-200c-mediated effects in the glomerulus are context-sensitive.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping