Single nephron proteomes connect morphology and function in proteinuric kidney disease

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 disease is a frequent and heterogeneous disease which affects 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 and patients 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, MS 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 the mutated gene product, nephrin. Up to 2000 proteins were quantified in an individual glomerulus.In conclusion we show that altered protein homeostasis (proteostasis) is a conserved key mechanism in proteinuric kidney diseases. Moreover, the “one‐nephron‐one‐proteome” technology developed here can capture intraindividual variability in diseases of the kidney and other tissues at a sub‐biopsy scale.Support or Funding InformationMMR was supported by the DFG.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.