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The Atypical Cyclin-Dependent Kinase 5 (Cdk5) Guards Podocytes from Apoptosis in Glomerular Disease While Being Dispensable for Podocyte Development
 
 
Article

A Tight Control of Non-Canonical TGF-β Pathways and MicroRNAs Downregulates Nephronectin in Podocytes

1
Department of Medicine 4–Nephrology and Hypertension, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
2
Research Center On Rare Kidney Diseases (RECORD), Universitätsklinikum Erlangen, 91054 Erlangen, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Laura Perin
Cells 2022, 11(1), 149; https://doi.org/10.3390/cells11010149
Received: 29 November 2021 / Revised: 22 December 2021 / Accepted: 1 January 2022 / Published: 3 January 2022
(This article belongs to the Special Issue New Aspects for Understanding Podocytopathies)
Nephronectin (NPNT) is an extracellular matrix protein in the glomerular basement membrane that is produced by podocytes and is important for the integrity of the glomerular filtration barrier. Upregulated transforming growth factor β (TGF-β) and altered NPNT are seen in different glomerular diseases. TGF-β downregulates NPNT and upregulates NPNT-targeting microRNAs (miRs). However, the pathways involved were previously unknown. By using selective inhibitors of the canonical, SMAD-dependent, and non-canonical TGF-β pathways, we investigated NPNT transcription, translation, secretion, and regulation through miRs in podocytes. TGF-β decreased NPNT mRNA and protein in cultured human podocytes. TGF-β-dependent regulation of NPNT was meditated through intracellular signaling pathways. Under baseline conditions, non-canonical pathways predominantly regulated NPNT post-transcriptionally. Podocyte NPNT secretion, however, was not dependent on canonical or non-canonical TGF-β pathways. The canonical TGF-β pathway was also dispensable for NPNT regulation after TGF-β stimulation, as TGF-β was still able to downregulate NPNT in the presence of SMAD inhibitors. In contrast, in the presence of different non-canonical pathway inhibitors, TGF-β stimulation did not further decrease NPNT expression. Moreover, distinct non-canonical TGF-β pathways mediated TGF-β-induced upregulation of NPNT-targeting miR-378a-3p. Thus, we conclude that post-transcriptional fine-tuning of NPNT expression in podocytes is mediated predominantly through non-canonical TGF-β pathways. View Full-Text
Keywords: podocytes; nephronectin; TGF-β; podocytopathies; post-transcriptional regulation; microRNAs podocytes; nephronectin; TGF-β; podocytopathies; post-transcriptional regulation; microRNAs
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MDPI and ACS Style

Sopel, N.; Ohs, A.; Schiffer, M.; Müller-Deile, J. A Tight Control of Non-Canonical TGF-β Pathways and MicroRNAs Downregulates Nephronectin in Podocytes. Cells 2022, 11, 149. https://doi.org/10.3390/cells11010149

AMA Style

Sopel N, Ohs A, Schiffer M, Müller-Deile J. A Tight Control of Non-Canonical TGF-β Pathways and MicroRNAs Downregulates Nephronectin in Podocytes. Cells. 2022; 11(1):149. https://doi.org/10.3390/cells11010149

Chicago/Turabian Style

Sopel, Nina, Alexandra Ohs, Mario Schiffer, and Janina Müller-Deile. 2022. "A Tight Control of Non-Canonical TGF-β Pathways and MicroRNAs Downregulates Nephronectin in Podocytes" Cells 11, no. 1: 149. https://doi.org/10.3390/cells11010149

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