PMID- 34716242
OWN - NLM
STAT- MEDLINE
DCOM- 20211214
LR  - 20230203
IS  - 1533-3450 (Electronic)
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 32
IP  - 11
DP  - 2021 Nov
TI  - Glomerular Endothelial Cell-Derived microRNA-192 Regulates Nephronectin 
      Expression in Idiopathic Membranous Glomerulonephritis.
PG  - 2777-2794
LID - 10.1681/ASN.2020121699 [doi]
AB  - 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.
CI  - Copyright (c) 2021 by the American Society of Nephrology.
FAU - Muller-Deile, Janina
AU  - Muller-Deile J
AD  - Department of Nephrology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 
      Erlangen, Germany.
FAU - Sopel, Nina
AU  - Sopel N
AD  - Department of Nephrology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 
      Erlangen, Germany.
FAU - Ohs, Alexandra
AU  - Ohs A
AD  - Department of Nephrology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 
      Erlangen, Germany.
FAU - Rose, Victoria
AU  - Rose V
AD  - Department of Nephrology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 
      Erlangen, Germany.
FAU - Groner, Marwin
AU  - Groner M
AD  - Research Center On Rare Kidney Diseases (RECORD), University Hospital Erlangen, 
      Erlangen, Germany.
FAU - Wrede, Christoph
AU  - Wrede C
AD  - Institute of Functional and Applied Anatomy, Medizinische Hochschule Hannover, 
      Hannover, Germany.
FAU - Hegermann, Jan
AU  - Hegermann J
AD  - Institute of Functional and Applied Anatomy, Medizinische Hochschule Hannover, 
      Hannover, Germany.
FAU - Daniel, Christoph
AU  - Daniel C
AD  - Department of Nephropathology, Friedrich-Alexander-University Erlangen-Nuremberg, 
      Erlangen, Germany.
FAU - Amann, Kerstin
AU  - Amann K
AD  - Department of Nephropathology, Friedrich-Alexander-University Erlangen-Nuremberg, 
      Erlangen, Germany.
FAU - Zahner, Gunther
AU  - Zahner G
AD  - Department of Medicine, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany.
FAU - Schiffer, Mario
AU  - Schiffer M
AD  - Department of Nephrology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, 
      Erlangen, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (Antigen-Antibody Complex)
RN  - 0 (Autoantigens)
RN  - 0 (Extracellular Matrix Proteins)
RN  - 0 (MIRN192 microRNA, human)
RN  - 0 (MIRN378 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Zebrafish Proteins)
RN  - 0 (nephronectin)
RN  - CKS1YQ9W1J (Gold Sodium Thiosulfate)
SB  - IM
MH  - Animals
MH  - Antigen-Antibody Complex/analysis
MH  - Autoantigens/genetics/immunology
MH  - Cells, Cultured
MH  - Coculture Techniques
MH  - Endothelial Cells/*metabolism
MH  - Exosomes/metabolism
MH  - Extracellular Matrix Proteins/*biosynthesis/deficiency/physiology
MH  - Gene Expression Regulation
MH  - Gene Targeting
MH  - Glomerular Basement 
      Membrane/immunology/*metabolism/*physiopathology/ultrastructure
MH  - Glomerulonephritis, Membranous/*genetics/immunology/metabolism/physiopathology
MH  - Gold Sodium Thiosulfate
MH  - Humans
MH  - Kidney Glomerulus/*metabolism
MH  - Metal Nanoparticles
MH  - Mice
MH  - MicroRNAs/biosynthesis/genetics/*physiology/urine
MH  - Paracrine Communication
MH  - Permeability
MH  - Podocytes/immunology/metabolism
MH  - Proteinuria/etiology
MH  - Transfection
MH  - Zebrafish
MH  - Zebrafish Proteins/deficiency/genetics
PMC - PMC8806098
OTO - NOTNLM
OT  - glomerular basement membrane
OT  - glomerular disease
OT  - glomerular endothelial cells
OT  - glomerular filtration barrier
OT  - membranous nephropathy
OT  - microRNAs
OT  - nephronectin
OT  - podocyte
EDAT- 2021/10/31 06:00
MHDA- 2021/12/15 06:00
PMCR- 2022/11/01
CRDT- 2021/10/30 05:39
PHST- 2020/12/05 00:00 [received]
PHST- 2021/07/09 00:00 [accepted]
PHST- 2021/10/30 05:39 [entrez]
PHST- 2021/10/31 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2022/11/01 00:00 [pmc-release]
AID - 00001751-202111000-00015 [pii]
AID - 2020121699 [pii]
AID - 10.1681/ASN.2020121699 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2021 Nov;32(11):2777-2794. doi: 10.1681/ASN.2020121699.