α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier
| العنوان: | α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier |
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| المؤلفون: | Manuel Rogg, Jasmin I. Maier, Clara Van Wymersch, Martin Helmstädter, Alena Sammarco, Maja Lindenmeyer, Paulina Zareba, Eloi Montanez, Gerd Walz, Martin Werner, Nicole Endlich, Thomas Benzing, Tobias B. Huber, Christoph Schell |
| المصدر: | J Am Soc Nephrol |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Mice, Knockout, Integrins, Mice, Basic Research, Glomerular Filtration Barrier, Podocytes, Nephrology, Microfilament Proteins, Animals, General Medicine |
| الوصف: | BACKGROUND: The cell-matrix adhesion between podocytes and the glomerular basement membrane is essential for the integrity of the kidney’s filtration barrier. Despite increasing knowledge about the complexity of integrin adhesion complexes, an understanding of the regulation of these protein complexes in glomerular disease remains elusive. METHODS: We mapped the in vivo composition of the podocyte integrin adhesome. In addition, we analyzed conditional knockout mice targeting a gene (Parva) that encodes an actin-binding protein (α-parvin), and murine disease models. To evaluate podocytes in vivo, we used super-resolution microscopy, electron microscopy, multiplex immunofluorescence microscopy, and RNA sequencing. We performed functional analysis of CRISPR/Cas9-generated PARVA single knockout podocytes and PARVA and PARVB double knockout podocytes in three- and two-dimensional cultures using specific extracellular matrix ligands and micropatterns. RESULTS: We found that PARVA is essential to prevent podocyte foot process effacement, detachment from the glomerular basement membrane, and the development of FSGS. Through the use of in vitro and in vivo models, we identified an inherent PARVB-dependent compensatory module at podocyte integrin adhesion complexes, sustaining efficient mechanical linkage at the filtration barrier. Sequential genetic deletion of PARVA and PARVB induces a switch in structure and composition of integrin adhesion complexes. This redistribution of these complexes translates into a loss of the ventral actin cytoskeleton, decreased adhesion capacity, impaired mechanical resistance, and dysfunctional extracellular matrix assembly. CONCLUSIONS: The findings reveal adaptive mechanisms of podocyte integrin adhesion complexes, providing a conceptual framework for therapeutic strategies to prevent podocyte detachment in glomerular disease. |
| تدمد: | 1533-3450 1046-6673 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ac28ef8d93627075668e3b5696733ac6 https://doi.org/10.1681/asn.2021101319 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ac28ef8d93627075668e3b5696733ac6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15333450 10466673 |
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