Single-nephron proteomes connect morphology and function in proteinuric kidney disease
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Single-nephron proteomes connect morphology and function in proteinuric kidney disease. / Höhne, Martin; Frese, Christian K; Grahammer, Florian; Dafinger, Claudia; Ciarimboli, Giuliano; Butt, Linus; Binz, Julia; Hackl, Matthias J; Rahmatollahi, Mahdieh; Kann, Martin; Schneider, Simon; Altintas, Mehmet M; Schermer, Bernhard; Reinheckel, Thomas; Göbel, Heike; Reiser, Jochen; Huber, Tobias B; Kramann, Rafael; Seeger-Nukpezah, Tamina; Liebau, Max C; Beck, Bodo B; Benzing, Thomas; Beyer, Andreas; Rinschen, Markus M.
In: KIDNEY INT, Vol. 93, No. 6, 06.2018, p. 1308-1319.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Single-nephron proteomes connect morphology and function in proteinuric kidney disease
AU - Höhne, Martin
AU - Frese, Christian K
AU - Grahammer, Florian
AU - Dafinger, Claudia
AU - Ciarimboli, Giuliano
AU - Butt, Linus
AU - Binz, Julia
AU - Hackl, Matthias J
AU - Rahmatollahi, Mahdieh
AU - Kann, Martin
AU - Schneider, Simon
AU - Altintas, Mehmet M
AU - Schermer, Bernhard
AU - Reinheckel, Thomas
AU - Göbel, Heike
AU - Reiser, Jochen
AU - Huber, Tobias B
AU - Kramann, Rafael
AU - Seeger-Nukpezah, Tamina
AU - Liebau, Max C
AU - Beck, Bodo B
AU - Benzing, Thomas
AU - Beyer, Andreas
AU - Rinschen, Markus M
N1 - Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
PY - 2018/6
Y1 - 2018/6
N2 - 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.
AB - 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.
KW - Animals
KW - Biological Variation, Individual
KW - Biomarkers
KW - Disease Models, Animal
KW - Extracellular Matrix Proteins
KW - Glomerulonephritis
KW - Humans
KW - Lysosome-Associated Membrane Glycoproteins
KW - Male
KW - Mice
KW - Mice, Knockout
KW - Nephrons
KW - Nephrotic Syndrome
KW - Podocytes
KW - Proteinuria
KW - Proteome
KW - Proteomics
KW - Proteostasis
KW - Repressor Proteins
KW - Reproducibility of Results
KW - Serum Albumin
KW - Tandem Mass Spectrometry
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/j.kint.2017.12.012
DO - 10.1016/j.kint.2017.12.012
M3 - SCORING: Journal article
C2 - 29530281
VL - 93
SP - 1308
EP - 1319
JO - KIDNEY INT
JF - KIDNEY INT
SN - 0085-2538
IS - 6
ER -
