PUBLICATION
Overexpression of TGF-β Inducible microRNA-143 in Zebrafish Leads to Impairment of the Glomerular Filtration Barrier by Targeting Proteoglycans
- Authors
- Müller-Deile, J., Gellrich, F., Schenk, H., Schroder, P., Nyström, J., Lorenzen, J., Haller, H., Schiffer, M.
- ID
- ZDB-PUB-161215-21
- Date
- 2016
- Source
- Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 40: 819-830 (Journal)
- Registered Authors
- Keywords
- Versican, Syndecan, Glycocalyx, micro-RNA-143, Podocytes, Zebrafish, Proteinuria, Glomerulus
- MeSH Terms
-
- Podocytes/drug effects
- Podocytes/metabolism
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- Transforming Growth Factor beta/pharmacology*
- PubMed
- 27941332 Full text @ Cell Physiol. Biochem.
Abstract
Background TGF-β is known as an important stress factor of podocytes in glomerular diseases. Apart from activation of direct pro-apoptotic pathways we wanted to analyze micro-RNA (miRs) driven regulation of components involved in the integrity of the glomerular filtration barrier induced by TGF-β. Since miR-143-3p (miR-143) is described as a TGF-β inducible miR in other cell types, we examined this specific miR and its ability to induce glomerular pathology.
Methods We analyzed miR-143 expression in cultured human podocytes after stimulation with TGF-β. We also microinjected zebrafish eggs with a miR-143 mimic or with morpholinos specific for its targets syndecan and versican and compared phenotype and proteinuria development.
Results We detected a time dependent, TGF-β inducible expression of miR-143 in human podocytes. Targets of miR-143 relevant in glomerular biology are syndecans and versican, which are known components of the glycocalyx. We found that syndecan 1 and 4 were predominantly expressed in podocytes while syndecan 3 was largely expressed in glomerular endothelial cells. Versican could be detected in both cell types. After injection of a miR-143 mimic in zebrafish larvae, syndecan 3, 4 and versican were significantly downregulated. Moreover, miR-143 overexpression or versican knockdown by morpholino caused loss of plasma proteins, edema, podocyte effacement and endothelial damage. In contrast, knockdown of syndecan 3 and syndecan 4 had no effects on glomerular filtration barrier.
Conclusion Expression of versican and syndecan isoforms is indispensable for proper barrier function. Podocyte-derived miR-143 is a mediator for paracrine and autocrine cross talk between podocytes and glomerular endothelial cells and can alter expression of glomerular glycocalyx proteins.
Genes / Markers
Figure Gallery (4 images)
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping