The molecular architecture of the kidney slit diaphragm

  • Vertebrate life depends on renal function to filter excess fluid and remove low-molecular-weight waste products. An essential component of the kidney filtration barrier is the slit diaphragm (SD), a specialized cell-cell junction between podocytes. Although the constituents of the SD are largely known, its molecular organization remains elusive. Here, we use super-resolution correlative light and electron microscopy to quantify a linear rate of reduction in albumin concentration across the filtration barrier under no-flow conditions. Next, we use cryo-electron tomography of vitreous lamellae from high-pressure frozen native glomeruli to analyze the molecular architecture of the SD. The resulting densities resemble a fishnet pattern. Fitting of Nephrin and Neph1, the main constituents of the SD, results in a complex interaction pattern with multiple contact sites between the molecules. Using molecular dynamics simulations, we construct a blueprint of the SD that explains its molecular architecture. Our architectural understanding of the SD reconciles previous findings and provides a mechanistic framework for the development of novel therapies to treat kidney dysfunction.

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Author:Alexandra N. BirtasuORCiD, Konstantin Wieland, Utz Heinrich ErmelORCiD, Johanna Viola RahmORCiDGND, Margot SchefferORCiDGND, Benjamin FlottmannGND, Mike HeilemannORCiDGND, Florian GrahammerORCiDGND, Achilleas S. FrangakisORCiDGND
URN:urn:nbn:de:hebis:30:3-794701
URL:https://www.biorxiv.org/content/10.1101/2023.10.27.564405v2
DOI:https://doi.org/10.1101/2023.10.27.564405
Parent Title (English):bioRxiv
Document Type:Preprint
Language:English
Date of Publication (online):2023/10/28
Date of first Publication:2023/10/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/02/13
Issue:2023.10.27.564405, Version 2
Edition:Version 2
Page Number:40
HeBIS-PPN:516147145
Institutes:Physik
Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Fachübergreifende Einrichtungen / Buchmann Institut für Molekulare Lebenswissenschaften (BMLS)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International