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Glycoproteomics of the Extracellular Matrix: A Method for Intact Glycopeptide Analysis Using Mass Spectrometry
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Proteomic Analysis Identifies Distinct Glomerular Extracellular Matrix in Collapsing Focal Segmental
Michael L Merchant1, Michelle T Barati2, Dawn J Caster2
1Division of Nephrology and Hypertension, Department of Medicine, University of Louisville, Louisville, Kentucky k.mcleish@louisville.edu michael.merchant@louisville.edu.
Journal of the American Society of Nephrology : JASN
|June 21, 2020
Summary
Collapsing FSGS (cFSGS) shows distinct glomerular extracellular matrix (ECM) changes compared to other FSGS variants. Activated parietal epithelial cells (PECs) and their cathepsins may drive these ECM alterations in cFSGS.
Area of Science:
- Nephrology
- Proteomics
- Glomerular disease research
Background:
- Mechanisms of extracellular matrix (ECM) replacement in focal segmental glomerulosclerosis (FSGS) variants are not fully understood.
- Histologic variants of FSGS, particularly collapsing FSGS (cFSGS), exhibit unique pathological features.
- Investigating differences in glomerular ECM composition between FSGS variants is crucial for understanding disease progression.
Purpose of the Study:
- To test the hypothesis that glomerular ECM composition differs between collapsing FSGS (cFSGS) and other FSGS variants.
- To identify specific ECM proteins and their localization in cFSGS.
- To explore the potential role of parietal epithelial cells (PECs) in ECM remodeling in cFSGS.
Main Methods:
- Proteomic analysis using mass spectrometry to quantify ECM proteins in glomeruli from FSGS patients and controls.
- Immunohistochemistry (IHC) and confocal microscopy for protein localization and verification.
- Gene expression analysis and quantification of urinary ECM proteins and peptides.
Main Results:
- Significant differences in 58 ECM proteins between cFSGS and FSGS not otherwise specified (FSGS-NOS), with 41 more abundant in cFSGS.
- Increased glomerular staining for cathepsin B, cathepsin C, and annexin A3 in cFSGS, colocalizing with activated PECs.
- Elevated urinary excretion of cathepsins and ECM-derived peptides in cFSGS compared to FSGS-NOS.
Conclusions:
- Glomerular sclerosis in cFSGS is characterized by distinct ECM composition compared to other FSGS variants.
- Infiltration of activated PECs and their associated cathepsins may contribute to aberrant ECM remodeling in cFSGS.
- Activated PECs and their cathepsins represent potential therapeutic targets for cFSGS.
Keywords:
cathepsincollapsing FSGSextracellular matrixfocal segmental glomerulosclerosisglomerular epithelial cellsMore Related Videos
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