A slit-diaphragm-associated protein network for dynamic control of renal filtration

Maciej K. Kocylowski, Hande Aypek, Wolfgang Bildl, Martin Helmstädter, Philipp Trachte, Bernhard Dumoulin, Sina Wittösch, Lukas Kühne, Ute Aukschun, Carolin Teetzen, Oliver Kretz, Botond Gaal, Akos Kulik, Corinne Antignac, Geraldine Mollet, Anna Köttgen, Burulca Göcmen, Jochen Schwenk, Uwe Schulte, Tobias B. Huber (), Bernd Fakler () and Florian Grahammer ()
Additional contact information
Maciej K. Kocylowski: University of Freiburg
Hande Aypek: University Medical Center Hamburg-Eppendorf
Wolfgang Bildl: University of Freiburg
Martin Helmstädter: University of Freiburg
Philipp Trachte: University of Freiburg
Bernhard Dumoulin: University Medical Center Hamburg-Eppendorf
Sina Wittösch: University Medical Center Hamburg-Eppendorf
Lukas Kühne: University of Freiburg
Ute Aukschun: University of Freiburg
Carolin Teetzen: University of Freiburg
Oliver Kretz: University Medical Center Hamburg-Eppendorf
Botond Gaal: University of Freiburg
Akos Kulik: University of Freiburg
Corinne Antignac: Paris Descartes University
Geraldine Mollet: Paris Descartes University
Anna Köttgen: University of Freiburg
Burulca Göcmen: University of Freiburg
Jochen Schwenk: University of Freiburg
Uwe Schulte: University of Freiburg
Tobias B. Huber: University Medical Center Hamburg-Eppendorf
Bernd Fakler: University of Freiburg
Florian Grahammer: University Medical Center Hamburg-Eppendorf

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The filtration of blood in the kidney which is crucial for mammalian life is determined by the slit-diaphragm, a cell-cell junction between the foot processes of renal podocytes. The slit-diaphragm is thought to operate as final barrier or as molecular sensor of renal filtration. Using high-resolution proteomic analysis of slit-diaphragms affinity-isolated from rodent kidney, we show that the native slit-diaphragm is built from the junction-forming components Nephrin, Neph1 and Podocin and a co-assembled high-molecular weight network of proteins. The network constituents cover distinct classes of proteins including signaling-receptors, kinases/phosphatases, transporters and scaffolds. Knockout or knock-down of either the core components or the selected network constituents tyrosine kinase MER (MERTK), atrial natriuretic peptide-receptor C (ANPRC), integral membrane protein 2B (ITM2B), membrane-associated guanylate-kinase, WW and PDZ-domain-containing protein1 (MAGI1) and amyloid protein A4 resulted in target-specific impairment or disruption of the filtration process. Our results identify the slit-diaphragm as a multi-component system that is endowed with context-dependent dynamics via a co-assembled protein network.

Date: 2022
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DOI: 10.1038/s41467-022-33748-1

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