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

Martin Höhne, Christian K. Frese, Florian Grahammer, Claudia Dafinger, Giuliano Ciarimboli, Linus Butt, Julia Binz, Matthias J. Hackl, Mahdieh Rahmatollahi, Martin Kann, Simon Schneider, Mehmet M. Altintas, Bernhard Schermer, Thomas Reinheckel, Heike Göbel, Jochen Reiser, Tobias B. Huber, Rafael Kramann, Tamina Seeger-Nukpezah, Max C. LiebauBodo B. Beck, Thomas Benzing, Andreas Beyer, Markus M. Rinschen

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1308-1319
Number of pages12
JournalKidney International
Volume93
Issue number6
DOIs
StatePublished - Jun 2018
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Nephrology

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