Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases

Kidney Int. 2017 Oct;92(4):836-849. doi: 10.1016/j.kint.2017.03.005. Epub 2017 May 3.

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.

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

Substances

  • 3' Untranslated Regions
  • Extracellular Matrix Proteins
  • MIRN378 microRNA, human
  • MicroRNAs
  • Morpholinos
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Vegfaa protein, zebrafish
  • Zebrafish Proteins
  • nephronectin