Regulation glomerulärer Matrixproteine durch podozytäre und endotheliale microRNAs
Zusammenfassung der Projektergebnisse
Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerolosclerosis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier is size selective and almost impermeable for antibodies. We found that podocyte-derived miR-378a-3p and glomerular endothelial cell-derived miR-192-5p regulate Nephronectin that is located in the glomerular basement membrane (GBM). Both miRs show an upregulated glomerular expression and can be detected in the urine of patients with iMGN. Reduced glomerular Nephronectin expression correlates with disease stage in patients with iMGN. Whole body knockdown of Nephronectin in zebrafish and podocyte-specific knockout of Nephronectin in mice results in structural damages of the glomerular basement membrane with increased lucidity of the lamina rara interna, which allows high molecular weight proteins up to the size of IgGs to pass. Reduced NPNT leading to leakiness of the GBM might therefore be an important part of the pathophysiology of iMGN. It might be an initiating step for antigen presentation of PLAR2 and allow auto-antibodies to reach podocyte antigens in iMGN. Furthermore, Nephronectin might be a prognostic parameter and miR- 378a-3p as well as miR-192-5p might be additional non-invasive markers in iMGN. Monitoring and targeting these miRs could be a promising diagnostic and therapeutic approach for iMGN in the future. Next to miRs, Transforming Growth Factor β (TGF-β) decreased Nephronectin mRNA and protein in cultured human podocytes. We found that TGF-β-dependent regulation of Nephronectin was meditated through intracellular signaling pathways. Under baseline condition, non-canonical pathways predominantly regulated Nephronectin post-transcriptionally. Podocyte Nephronectin secretion however was not dependent on neither canonical nor non-canonical TGF-β pathways. The canonical TGF-β pathway was also dispensable for Nephronectin regulation after TGF-β stimulation, as TGF-β was still able to downregulate Nephronectin in the presence of SMAD inhibitors. In contrast, in the presence of different non-canonical pathways inhibitors TGF-β stimulation had no effect on Nephronectin any longer. Furthermore, distinct non-canonical TGF-β pathways mediated TGF-βinduced upregulation of Nephronectin-targeting miR-378a-3p. Thus, post-transcriptional fine-tuning of Nephronectin expression in podocytes is mediated predominantly through non-canonical TGF-β pathways. As TGF-β and Nephronectin are dysregulated in different glomerular diseases our results of a TGF-β-mediated Nephronectin regulation facilitated mainly by non-canonical pathways and posttranscriptional mechanisms might have important impact for the development of novel therapeutic strategies in the future.
Projektbezogene Publikationen (Auswahl)
- Overexpression of preeclampsia induced microRNA-26a-5p leads to proteinuria in zebrafish. Sci Rep 2018; 8: 3621-018-22070-w.43
Müller-Deile J, Schroder P, Beverly-Staggs L, et al.
(Siehe online unter https://doi.org/10.1038/s41598-018-22070-w) - Circulating factors cause proteinuria in parabiotic zebrafish. Kidney Int 2019; 96: 342-349
Müller-Deile J, Schenk H, Schroder P, et al.
(Siehe online unter https://doi.org/10.1016/j.kint.2019.02.013) - Identification of cell and disease specific microRNAs in glomerular pathologies. J Cell Mol Med. 2019;23(6):3927-3939
Müller-Deile J, Dannenberg J, Liu P, et al.
(Siehe online unter https://doi.org/10.1111/jcmm.14270) - The Zebrafish Model to Understand Epigenetics in Renal Diseases. Int J Mol Sci. 2021;22(17):9152
Sopel N, Müller-Deile J
(Siehe online unter https://doi.org/10.3390/ijms22179152)
