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.
Cell reports. 2018 May 22 [Epub]
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 Busch, Mario Schiffer, Carsten Bergmann, Marcus Krüger, Friedhelm Hildebrandt, Joern Dengjel, Thomas Benzing, Tobias B Huber
Department II of Internal Medicine, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, 50931 Cologne, Germany. Electronic address: ., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany., Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany., Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, 79104 Freiburg, Germany; Center for Systems Biology (ZBSA), Albert Ludwigs University, 79104 Freiburg, Germany., Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Department II of Internal Medicine, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany., Department of Medicine/Nephrology, Hannover Medical School, 30625 Hannover, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04609, USA., Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04609, USA; Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea., Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Center for Human Genetics, Bioscientia, 55218 Ingelheim, Germany., Department II of Internal Medicine, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, 50931 Cologne, Germany., Department for Neuroanatomy, University of Freiburg, 79104 Freiburg, Germany; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, 79104 Freiburg, Germany; Department of Dermatology, Medical Center - University of Freiburg, 79106 Freiburg, Germany., Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, 79106 Freiburg, Germany; German Cancer Consortium (DKTK), 79106 Freiburg, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, 79106 Freiburg, Germany; Lübeck Institute for Experimental Dermatology (LIED), University of Lübeck, 23562 Lübeck, Germany., Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; Center for Human Genetics, Bioscientia, 55218 Ingelheim, Germany., Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany., Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, 79104 Freiburg, Germany; Center for Systems Biology (ZBSA), Albert Ludwigs University, 79104 Freiburg, Germany; Department of Dermatology, Medical Center - University of Freiburg, 79106 Freiburg, Germany; Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland; BIOSS Centre for Biological Signaling Studies, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany., Department II of Internal Medicine, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, 50931 Cologne, Germany. Electronic address: ., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, 79104 Freiburg, Germany; Center for Systems Biology (ZBSA), Albert Ludwigs University, 79104 Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany. Electronic address: .