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

Müller-Deile J, Sopel N, Ohs A, Rose V, Gröner M, Wrede C, Hegermann J, Daniel C, Amann KU, Zahner G, Schiffer M (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Journal of the American Society of Nephrology American Society of Nephrology

Book Volume: 32

Pages Range: 2777-2794

Journal Issue: 11

DOI: 10.1681/ASN.2020121699

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 with CRIS profile

Janina Müller-Deile Department of Medicine 4 – Nephrology and Hypertension Nina Sopel Professur für Molekulare Pneumologie Alexandra Ohs Institut für Biomedizin des Alterns Victoria Rose Department of Medicine 4 – Nephrology and Hypertension Marwin Gröner Lehrstuhl für Innere Medizin IV Christoph Daniel Medizinische Fakultät Kerstin Ute Amann Professur für Nephropathologie Mario Schiffer Lehrstuhl für Innere Medizin IV

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

F009: Generation of novel 3D co-culture systems for study of glomerular functions ex vivo June 16, 2020 - June 15, 2023

Involved external institutions

Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE)

How to cite

APA:

Müller-Deile, J., Sopel, N., Ohs, A., Rose, V., Gröner, M., Wrede, C.,... Schiffer, M. (2021). Glomerular Endothelial Cell-Derived microRNA-192 Regulates Nephronectin Expression in Idiopathic Membranous Glomerulonephritis. Journal of the American Society of Nephrology, 32(11), 2777-2794. https://doi.org/10.1681/ASN.2020121699

MLA:

Müller-Deile, Janina, et al. "Glomerular Endothelial Cell-Derived microRNA-192 Regulates Nephronectin Expression in Idiopathic Membranous Glomerulonephritis." Journal of the American Society of Nephrology 32.11 (2021): 2777-2794.

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