Α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier. Issue 4 (April 2022)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of the American Society of Nephrology. Volume 33:Issue 4(2022)
• Page Start: 786
• Page End: 808
• Publication Date: 2022-04
• Subjects: focal segmental glomerulosclerosis -- glomerular epithelial cells -- podocyte -- proteinuria -- integrin adhesion complex -- IPP complex -- PARVA -- glomerular filtration barrier -- PARVB -- focal adhesion
• DOI: 10.1681/ASN.2021101319
• Languages: English
• ISSNs: 1046-6673

Abstract

Significance Statement: Although podocyte detachment is a well-established factor driving the progression of glomerular kidney diseases, the underlying mechanisms initiating podocyte loss remain elusive. In particular, the co-occurrence of podocyte detachment and adaptive reinforcement of the actin cytoskeleton and integrin adhesion complexes presents a conundrum. The authors provide a comprehensive map of the podocyte adhesome and identify an actin-binding adhesome protein, α-parvin (PARVA), as a podocyte-specific mechanical linker. By employing a complementary approach involving both in vivo and in vitro models, they demonstrate that PARVA prevents podocyte detachment via mechano-adaptive remodeling of adhesion complexes. These observations suggest that insufficient linkage of a tensile actin cytoskeleton to integrin adhesion complexes is a causative mechanism in podocyte detachment in glomerular diseases. Visual Abstract: 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 P ARVB 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.