a-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier

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 com- plexity 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 ana- lyzed conditional knockout mice targeting a gene (Parva) that encodes an actin-binding protein (a-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.

Automated summary

This study investigated the composition and regulation of podocyte integrin adhesion complexes and identified the important roles of PARVA and PARVB in maintaining the integrity of the filtration barrier. By using gene knockout experiments, the researchers revealed the impact of these proteins on podocytes and uncovered the adaptive mechanisms of podocyte integrin adhesion complexes.