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

Journal article
Authors J. Muller-Deile
J. Dannenberg
P. Schroder
M. H. Lin
J. H. Miner
R. J. Chen
J. H. Brasen
T. Thum
Jenny Nyström
L. B. Staggs
H. Haller
J. Fiedler
J. M. Lorenzen
M. Schiffer
Published in Kidney International
Volume 92
Issue 4
Pages 836-849
ISSN 0085-2538
Publication year 2017
Published at Institute of Neuroscience and Physiology
Pages 836-849
Language en
Links doi.org/10.1016/j.kint.2017.03.005
Keywords glomerular basement membrane, membranous glomerulone-phropathy, microRNA, nephronectin, podocytes, focal segmental glomerulosclerosis, extracellular-matrix, kidney, development, down-regulation, messenger-rna, expression, micrornas, nephropathy, zebrafish, gene, Urology & Nephrology
Subject categories Clinical Medicine

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.

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