α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier
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 g...
Saved in:
Published in | Journal of the American Society of Nephrology Vol. 33; no. 4; pp. 786 - 808 |
---|---|
Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society of Nephrology
01.04.2022
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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.
We mapped the
composition of the podocyte integrin adhesome. In addition, we analyzed conditional knockout mice targeting a gene (
) that encodes an actin-binding protein (α-parvin), and murine disease models. To evaluate podocytes
, we used super-resolution microscopy, electron microscopy, multiplex immunofluorescence microscopy, and RNA sequencing. We performed functional analysis of CRISPR/Cas9-generated
single knockout podocytes and
and P
double knockout podocytes in three- and two-dimensional cultures using specific extracellular matrix ligands and micropatterns.
We found that
is essential to prevent podocyte foot process effacement, detachment from the glomerular basement membrane, and the development of FSGS. Through the use of
and
models, we identified an inherent
-dependent compensatory module at podocyte integrin adhesion complexes, sustaining efficient mechanical linkage at the filtration barrier. Sequential genetic deletion of
and
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.
The findings reveal adaptive mechanisms of podocyte integrin adhesion complexes, providing a conceptual framework for therapeutic strategies to prevent podocyte detachment in glomerular disease. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1046-6673 1533-3450 |
DOI: | 10.1681/ASN.2021101319 |