Universität zu Köln

Rogg, Manuel ORCID: 0000-0002-6658-9159, Maier, Jasmin I., Van Wymersch, Clara, Helmstaedter, Martin, Sammarco, Alena, Lindenmeyer, Maja, Zareba, Paulina, Montanez, Eloi ORCID: 0000-0003-4059-5056, Walz, Gerd, Werner, Martin, Endlich, Nicole, Benzing, Thomas ORCID: 0000-0003-0512-1066, Huber, Tobias B. and Schell, Christoph ORCID: 0000-0001-5344-624X (2022). a-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier. J. Am. Soc. Nephrol., 33 (4). S. 786 - 809. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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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 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rogg, Manuel UNSPECIFIED orcid.org/0000-0002-6658-9159 UNSPECIFIED Maier, Jasmin I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Van Wymersch, Clara UNSPECIFIED UNSPECIFIED UNSPECIFIED Helmstaedter, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Sammarco, Alena UNSPECIFIED UNSPECIFIED UNSPECIFIED Lindenmeyer, Maja UNSPECIFIED UNSPECIFIED UNSPECIFIED Zareba, Paulina UNSPECIFIED UNSPECIFIED UNSPECIFIED Montanez, Eloi UNSPECIFIED orcid.org/0000-0003-4059-5056 UNSPECIFIED Walz, Gerd UNSPECIFIED UNSPECIFIED UNSPECIFIED Werner, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Endlich, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED orcid.org/0000-0003-0512-1066 UNSPECIFIED Huber, Tobias B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schell, Christoph UNSPECIFIED orcid.org/0000-0001-5344-624X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-689180
DOI:	10.1681/ASN.2021101319
Journal or Publication Title:	J. Am. Soc. Nephrol.
Volume:	33
Number:	4
Page Range:	S. 786 - 809
Date:	2022
Publisher:	AMER SOC NEPHROLOGY
Place of Publication:	WASHINGTON
ISSN:	1533-3450
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FOOT PROCESS EFFACEMENT; LINKED KINASE; KIDNEY-DISEASE; STRESS FIBERS; ALPHA-ACTININ-4; EXPRESSION; DETACHMENT; PODOCYTES; REVEALS; PROTEIN Multiple languages Urology & Nephrology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68918