ZFIN ID: ZDB-PUB-170510-23
Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases
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.
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.
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.