A Multi-layered Quantitative In Vivo Expression Atlas of the Podocyte Unravels Kidney Disease Candidate Genes

Markus M Rinschen, Markus Gödel, Florian Grahammer, Stefan Zschiedrich, Martin Helmstädter, Oliver Kretz, Mostafa Zarei, Daniela A Braun, Sebastian Dittrich, Caroline Pahmeyer, Patricia Schroder, Carolin Teetzen, HeonYung Gee, Ghaleb Daouk, Martin Pohl, Elisa Kuhn, Bernhard Schermer, Victoria Küttner, Melanie Boerries, Hauke BuschMario Schiffer, Carsten Bergmann, Marcus Krüger, Friedhelm Hildebrandt, Joern Dengjel, Thomas Benzing, Tobias B Huber

Abstract

Damage to and loss of glomerular podocytes has been identified as the culprit lesion in progressive kidney diseases. Here, we combine mass spectrometry-based proteomics with mRNA sequencing, bioinformatics, and hypothesis-driven studies to provide a comprehensive and quantitative map of mammalian podocytes that identifies unanticipated signaling pathways. Comparison of the in vivo datasets with proteomics data from podocyte cell cultures showed a limited value of available cell culture models. Moreover, in vivo stable isotope labeling by amino acids uncovered surprisingly rapid synthesis of mitochondrial proteins under steady-state conditions that was perturbed under autophagy-deficient, disease-susceptible conditions. Integration of acquired omics dimensions suggested FARP1 as a candidate essential for podocyte function, which could be substantiated by genetic analysis in humans and knockdown experiments in zebrafish. This work exemplifies how the integration of multi-omics datasets can identify a framework of cell-type-specific features relevant for organ health and disease.

OriginalspracheEnglisch
ZeitschriftCell Reports
Jahrgang23
Ausgabenummer8
Seiten (von - bis)2495-2508
Seitenumfang14
DOIs
PublikationsstatusVeröffentlicht - 2018

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