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α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier.
Rogg, Manuel; Maier, Jasmin I; Van Wymersch, Clara; Helmstädter, Martin; Sammarco, Alena; Lindenmeyer, Maja; Zareba, Paulina; Montanez, Eloi; Walz, Gerd; Werner, Martin; Endlich, Nicole; Benzing, Thomas; Huber, Tobias B; Schell, Christoph.
  • Rogg M; Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
  • Maier JI; Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
  • Van Wymersch C; Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
  • Helmstädter M; Department of Medicine IV, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
  • Sammarco A; Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
  • Lindenmeyer M; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Zareba P; Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
  • Montanez E; Department of Physiological Sciences, Faculty of Medicine, University of Barcelona and Health Sciences and Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
  • Walz G; Department of Medicine IV, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
  • Werner M; Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
  • Endlich N; Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
  • Benzing T; Center of High-End Imaging, NIPOKA GmbH, Greifswald, Germany.
  • Huber TB; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
  • Schell C; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
J Am Soc Nephrol ; 33(4): 786-808, 2022 04.
Статья в английский | MEDLINE | ID: covidwho-2141050
ABSTRACT

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.
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Полный текст: Имеется в наличии Коллекция: Международные базы данных база данных: MEDLINE Основная тема: Podocytes / Glomerular Filtration Barrier / Microfilament Proteins Тип исследования: Экспериментальные исследования Пределы темы: Животные Язык: английский Журнал: J Am Soc Nephrol Тематика журнала: Нефрология Год: 2022 Тип: Статья Аффилированная страна: Asn.2021101319

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Полный текст: Имеется в наличии Коллекция: Международные базы данных база данных: MEDLINE Основная тема: Podocytes / Glomerular Filtration Barrier / Microfilament Proteins Тип исследования: Экспериментальные исследования Пределы темы: Животные Язык: английский Журнал: J Am Soc Nephrol Тематика журнала: Нефрология Год: 2022 Тип: Статья Аффилированная страна: Asn.2021101319