Hoehne, 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 ORCID: 0000-0002-5194-9000, Reinheckel, Thomas ORCID: 0000-0001-9866-9105, Goebel, Heike, Reiser, Jochen, Huber, Tobias B. ORCID: 0000-0001-7175-5062, Kramann, Rafael, Seeger-Nukpezah, Tamina, Liebau, Max C., Beck, Bodo B., Benzing, Thomas, Beyer, Andreas ORCID: 0000-0002-3891-2123 and Rinschen, Markus M. (2018). Single-nephron proteomes connect morphology and function in proteinuric kidney disease. Kidney Int., 93 (6). S. 1308 - 1320. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1523-1755

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hoehne, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frese, Christian K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grahammer, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dafinger, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ciarimboli, GiulianoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Butt, LinusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Binz, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hackl, Matthias J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rahmatollahi, MahdiehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kann, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altintas, Mehmet M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermer, BernhardUNSPECIFIEDorcid.org/0000-0002-5194-9000UNSPECIFIED
Reinheckel, ThomasUNSPECIFIEDorcid.org/0000-0001-9866-9105UNSPECIFIED
Goebel, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiser, JochenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huber, Tobias B.UNSPECIFIEDorcid.org/0000-0001-7175-5062UNSPECIFIED
Kramann, RafaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger-Nukpezah, TaminaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liebau, Max C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beck, Bodo B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benzing, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beyer, AndreasUNSPECIFIEDorcid.org/0000-0002-3891-2123UNSPECIFIED
Rinschen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-183582
DOI: 10.1016/j.kint.2017.12.012
Journal or Publication Title: Kidney Int.
Volume: 93
Number: 6
Page Range: S. 1308 - 1320
Date: 2018
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1523-1755
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PHOSPHOPROTEOMIC ANALYSIS; COMPUTATIONAL PLATFORM; ANALYSIS REVEALS; CATHEPSIN-B; QUANTIFICATION; PODOCYTES; CLASSIFICATION; IDENTIFICATION; ENDOCYTOSIS; VALIDATIONMultiple languages
Urology & NephrologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18358

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