PUBLICATION
Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases
- Authors
- Müller-Deile, J., Dannenberg, J., Schroder, P., Lin, M.H., Miner, J.H., Chen, R., Bräsen, J.H., Thum, T., Nyström, J., Staggs, L.B., Haller, H., Fiedler, J., Lorenzen, J.M., Schiffer, M.
- ID
- ZDB-PUB-170510-23
- Date
- 2017
- Source
- Kidney International 92(4): 836-849 (Journal)
- Registered Authors
- Keywords
- glomerular basement membrane, membranous glomerulonephropathy, microRNA, nephronectin, podocytes
- MeSH Terms
-
- 3' Untranslated Regions/genetics
- Animals
- Biopsy
- Disease Models, Animal
- Down-Regulation
- Extracellular Matrix Proteins/genetics*
- Extracellular Matrix Proteins/metabolism
- Gene Knockdown Techniques/methods
- Glomerular Basement Membrane/metabolism*
- Glomerular Basement Membrane/pathology
- Glomerulonephritis, Membranous/genetics*
- Glomerulonephritis, Membranous/pathology
- Glomerulonephritis, Membranous/urine
- Glomerulosclerosis, Focal Segmental/genetics*
- Glomerulosclerosis, Focal Segmental/pathology
- Glomerulosclerosis, Focal Segmental/urine
- Humans
- Male
- Mice
- MicroRNAs/genetics
- MicroRNAs/metabolism*
- Morpholinos/metabolism
- Podocytes/metabolism
- Podocytes/pathology
- Proteinuria/genetics
- Proteinuria/pathology
- Up-Regulation
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 28476557 Full text @ Kidney Int.
Citation
Müller-Deile, J., Dannenberg, J., Schroder, P., Lin, M.H., Miner, J.H., Chen, R., Bräsen, J.H., Thum, T., Nyström, J., Staggs, L.B., Haller, H., Fiedler, J., Lorenzen, J.M., Schiffer, M. (2017) Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases. Kidney International. 92(4):836-849.
Abstract
The pathophysiology of many proteinuric kidney diseases is poorly understood, and microRNAs (miRs) regulation of these diseases has been largely unexplored. Here, we tested whether miR-378a-3p is a novel regulator of glomerular diseases. MiR-378a-3p has two predicted targets relevant to glomerular function, the glomerular basement membrane matrix component, nephronectin (NPNT), and vascular endothelial growth factor VEGF-A. In zebrafish (Danio rerio), miR-378a-3p mimic injection or npnt knockdown by a morpholino oligomer caused an identical phenotype consisting of edema, proteinuria, podocyte effacement, and widening of the glomerular basement membrane in the lamina rara interna. Zebrafish vegf-A protein could not rescue this phenotype. However, mouse Npnt constructs containing a mutated 3'UTR region prevented the phenotype caused by miR-378a-3p mimic injection. Overexpression of miR-378a-3p in mice confirmed glomerular dysfunction in a mammalian model. Biopsies from patients with focal segmental glomerulosclerosis and membranous nephropathy had increased miR-378a-3p expression and reduced glomerular levels of NPNT. Thus, miR-378a-3p-mediated suppression of the glomerular matrix protein NPNT is a novel mechanism for proteinuria development in active glomerular diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping