Abstract: PO1705
Glomerular Endothelial Cell-Derived MicroRNA-192 Regulates Podocyte Nephronectin in Membranous Glomerulonephritis
Session Information
- Podocyte Pathobiology: Basic Science Studies and Animal Models
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Müller-Deile, Janina, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
- Sopel, Nina, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
- Rose, Victoria, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
- Daniel, Christoph, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
- Amann, Kerstin U., Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
- Schiffer, Mario, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
Background
Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). It remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier (GFB) is normally size-selective and impermeable for antibodies.
Methods
Kidney biopsies from patients with iMGN, cell culture, zebrafish and mice 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 glomeruli of patients with iMGN whereas NPNT expression is reduced. Overexpression miR-192-5p as well as morpholino-mediated npnt knockdown induced edema, proteinuria and podocyte effacement similar to podocyte-derived miR-378a-3p in zebrafish. Moreover, structural changes of the glomerular basement membrane (GBM) with increased lucidity, slicing and lamellation especially of the lamina rara interna similar to ultrastructural findings seen in advanced stages of iMGN were found (Fig. 1). 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 secretion of miR-192-5p containing exosomes in a paracrine manner.
Conclusion
Podocyte NPNT is important for proper GFB 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 part of the pathophysiology of iMGN and enables subepithelial immune complex deposition in iMGN.
Fig. 1