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

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.

• Authors: 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
• Journal: Kidney international (Kidney Int) Vol. 92 Issue 4 Pg. 836-849 (10 2017) ISSN: 1523-1755 [Electronic] United States
• PMID: 28476557 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Biopsy
• Disease Models, Animal
• Down-Regulation
• Extracellular Matrix Proteins (genetics, metabolism)
• Gene Knockdown Techniques (methods)
• Glomerular Basement Membrane (metabolism, pathology)
• Glomerulonephritis, Membranous (genetics, pathology, urine)
• Glomerulosclerosis, Focal Segmental (genetics, pathology, urine)
• Humans
• Male
• Mice
• MicroRNAs (genetics, metabolism)
• Morpholinos (metabolism)
• Podocytes (metabolism, pathology)
• Proteinuria (genetics, pathology)
• Up-Regulation
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Zebrafish
• Zebrafish Proteins (genetics, metabolism)