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Kidney Int. 2018 Jun;93(6):1308-1319. doi: 10.1016/j.kint.2017.12.012. Epub 2018 Mar 9.

Single-nephron proteomes connect morphology and function in proteinuric kidney disease.

Author information

1
Department II of Internal Medicine, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany.
2
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
3
III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
4
Department II of Internal Medicine, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Department of Pediatrics, Division of Pediatric Nephrology, University Hospital of Cologne, Cologne, Germany.
5
Department of Internal Medicine D, Münster, Germany.
6
Department II of Internal Medicine, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
7
Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
8
Rush University Medical Center, Chicago, Illinois, USA.
9
Institut of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies and Center for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University, Freiburg, Germany.
10
Institute of Pathology, University Hospital Cologne, Cologne, Germany.
11
III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies and Center for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University, Freiburg, Germany.
12
Division of Nephrology, RWTH Aachen University, Aachen, Germany.
13
Department I of Internal Medicine, University of Cologne, Cologne, Germany.
14
Department II of Internal Medicine, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany; Department of Pediatrics, Division of Pediatric Nephrology, University Hospital of Cologne, Cologne, Germany.
15
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Department of Human Genetics, University Hospital Cologne, Cologne, Germany.
16
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany.
17
Department II of Internal Medicine, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany. Electronic address: markus.rinschen@uk-koeln.de.

Abstract

In diseases of many parenchymatous organs, heterogeneous deterioration of individual functional units determines the clinical prognosis. However, the molecular characterization at the level of such individual subunits remains a technological challenge that needs to be addressed in order to better understand pathological mechanisms. Proteinuric glomerular kidney diseases are frequent and assorted diseases affecting a fraction of glomeruli and their draining tubules to variable extents, and for which no specific treatment exists. Here, we developed and applied a mass spectrometry-based methodology to investigate heterogeneity of proteomes from individually isolated nephron segments from mice with proteinuric kidney disease. In single glomeruli from two different mouse models of sclerotic glomerular disease, we identified a coherent protein expression module consisting of extracellular matrix protein deposition (reflecting glomerular sclerosis), glomerular albumin (reflecting proteinuria) and LAMP1, a lysosomal protein. This module was associated with a loss of podocyte marker proteins while genetic ablation of LAMP1-correlated lysosomal proteases could ameliorate glomerular damage in vivo. Furthermore, proteomic analyses of individual glomeruli from patients with genetic sclerotic and non-sclerotic proteinuric diseases revealed increased abundance of lysosomal proteins, in combination with a decreased abundance of mutated gene products. Thus, altered protein homeostasis (proteostasis) is a conserved key mechanism in proteinuric kidney diseases. Moreover, our technology can capture intra-individual variability in diseases of the kidney and other tissues at a sub-biopsy scale.

KEYWORDS:

albuminuria; focal segmental glomerulosclerosis; glomerulus proteomic analysis; podocyte; proximal tubule

PMID:
29530281
DOI:
10.1016/j.kint.2017.12.012
[Indexed for MEDLINE]

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