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

Janina Müller-Deile, Jan Dannenberg, Patricia Schroder, Meei Hua Lin, Jeffrey H. Miner, Rongjun Chen, Jan Hinrich Bräsen, Thomas Thum, Jenny Nyström, Lynne Beverly Staggs, Hermann Haller, Jan Fiedler, Johan M. Lorenzen, Mario Schiffer

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish
Pages (from-to)836-849
Number of pages14
JournalKidney International
Volume92
Issue number4
DOIs
StatePublished - Oct 2017

Keywords

  • glomerular basement membrane
  • membranous glomerulonephropathy
  • microRNA
  • nephronectin
  • podocytes

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    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. https://doi.org/10.1016/j.kint.2017.03.005