Glomerular Endothelial Cell-Derived microRNA-192 Regulates Nephronectin Expression in Idiopathic Membranous Glomerulonephritis.

Abstract

BACKGROUND:

Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier (GFB) is size selective and almost impermeable for antibodies.

METHODS:

Kidney biopsies from patients with iMGN, cell culture, zebrafish, and mouse models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the GFB.

RESULTS:

Glomerular endothelial cell (GEC)-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in urine and glomeruli of patients with iMGN, whereas glomerular NPNT is reduced. Overexpression of miR-192-5p and morpholino-mediated npnt knockdown induced edema, proteinuria, and podocyte effacement similar to podocyte-derived miR-378a-3p in zebrafish. Structural changes of the glomerular basement membrane (GBM) with increased lucidity, splitting, and lamellation, especially of the lamina rara interna, similar to ultrastructural findings seen in advanced stages of iMGN, were found. IgG-size nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt-knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte-specific Npnt knockout mice. GECs downregulate podocyte NPNT by transfer of miR-192-5p-containing exosomes in a paracrine manner.

CONCLUSIONS:

Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by GEC-derived miR-192-5p and podocyte-derived miR-378a-3p. We hypothesize that loss of NPNT in the GBM is an important part of the initial pathophysiology of iMGN and enables autoantigenicity of podocyte antigens and subepithelial immune complex deposition in iMGN.

• Authors: Janina Müller-Deile, Nina Sopel, Alexandra Ohs, Victoria Rose, Marwin Gröner, Christoph Wrede, Jan Hegermann, Christoph Daniel, Kerstin Amann, Gunther Zahner, Mario Schiffer
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 32 Issue 11 Pg. 2777-2794 (11 2021) ISSN: 1533-3450 [Electronic] United States
• PMID: 34716242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by the American Society of Nephrology.

Chemical References

• Antigen-Antibody Complex
• Autoantigens
• Extracellular Matrix Proteins
• MIRN192 microRNA, human
• MIRN378 microRNA, human
• MicroRNAs
• Zebrafish Proteins
• nephronectin
• Gold Sodium Thiosulfate

Topics

• Animals
• Antigen-Antibody Complex (analysis)
• Autoantigens (genetics, immunology)
• Cells, Cultured
• Coculture Techniques
• Endothelial Cells (metabolism)
• Exosomes (metabolism)
• Extracellular Matrix Proteins (biosynthesis, deficiency, physiology)
• Gene Expression Regulation
• Gene Targeting
• Glomerular Basement Membrane (immunology, metabolism, physiopathology, ultrastructure)
• Glomerulonephritis, Membranous (genetics, immunology, metabolism, physiopathology)
• Gold Sodium Thiosulfate
• Humans
• Kidney Glomerulus (metabolism)
• Metal Nanoparticles
• Mice
• MicroRNAs (biosynthesis, genetics, physiology, urine)
• Paracrine Communication
• Permeability
• Podocytes (immunology, metabolism)
• Proteinuria (etiology)
• Transfection
• Zebrafish
• Zebrafish Proteins (deficiency, genetics)