Proteomic Analysis Identifies Distinct Glomerular Extracellular Matrix in Collapsing Focal Segmental Glomerulosclerosis
Copyright © 2020 by the American Society of Nephrology..
BACKGROUND: The mechanisms leading to extracellular matrix (ECM) replacement of areas of glomerular capillaries in histologic variants of FSGS are unknown. This study used proteomics to test the hypothesis that glomerular ECM composition in collapsing FSGS (cFSGS) differs from that of other variants.
METHODS: ECM proteins in glomeruli from biopsy specimens of patients with FSGS not otherwise specified (FSGS-NOS) or cFSGS and from normal controls were distinguished and quantified using mass spectrometry, verified and localized using immunohistochemistry (IHC) and confocal microscopy, and assessed for gene expression. The analysis also quantified urinary excretion of ECM proteins and peptides.
RESULTS: Of 58 ECM proteins that differed in abundance between cFSGS and FSGS-NOS, 41 were more abundant in cFSGS and 17 in FSGS-NOS. IHC showed that glomerular tuft staining for cathepsin B, cathepsin C, and annexin A3 in cFSGS was significantly greater than in other FSGS variants, in minimal change disease, or in membranous nephropathy. Annexin A3 colocalized with cathepsin B and C, claudin-1, phosphorylated ERK1/2, and CD44, but not with synaptopodin, in parietal epithelial cells (PECs) infiltrating cFSGS glomeruli. Transcripts for cathepsins B and C were increased in FSGS glomeruli compared with normal controls, and urinary excretion of both cathepsins was significantly greater in cFSGS compared with FSGS-NOS. Urinary excretion of ECM-derived peptides was enhanced in cFSGS, although in silico analysis did not identify enhanced excretion of peptides derived from cathepsin B or C.
CONCLUSIONS: ECM differences suggest that glomerular sclerosis in cFSGS differs from that in other FSGS variants. Infiltration of activated PECs may disrupt ECM remodeling in cFSGS. These cells and their cathepsins may be therapeutic targets.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:31 |
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| Enthalten in: |
Journal of the American Society of Nephrology : JASN - 31(2020), 8 vom: 08. Aug., Seite 1883-1904 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Merchant, Michael L [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.03.2021 Date Revised 02.08.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1681/ASN.2019070696 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Merchant, Michael L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Proteomic Analysis Identifies Distinct Glomerular Extracellular Matrix in Collapsing Focal Segmental Glomerulosclerosis |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 02.03.2021 | ||
| 500 | |a Date Revised 02.08.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 by the American Society of Nephrology. | ||
| 520 | |a BACKGROUND: The mechanisms leading to extracellular matrix (ECM) replacement of areas of glomerular capillaries in histologic variants of FSGS are unknown. This study used proteomics to test the hypothesis that glomerular ECM composition in collapsing FSGS (cFSGS) differs from that of other variants | ||
| 520 | |a METHODS: ECM proteins in glomeruli from biopsy specimens of patients with FSGS not otherwise specified (FSGS-NOS) or cFSGS and from normal controls were distinguished and quantified using mass spectrometry, verified and localized using immunohistochemistry (IHC) and confocal microscopy, and assessed for gene expression. The analysis also quantified urinary excretion of ECM proteins and peptides | ||
| 520 | |a RESULTS: Of 58 ECM proteins that differed in abundance between cFSGS and FSGS-NOS, 41 were more abundant in cFSGS and 17 in FSGS-NOS. IHC showed that glomerular tuft staining for cathepsin B, cathepsin C, and annexin A3 in cFSGS was significantly greater than in other FSGS variants, in minimal change disease, or in membranous nephropathy. Annexin A3 colocalized with cathepsin B and C, claudin-1, phosphorylated ERK1/2, and CD44, but not with synaptopodin, in parietal epithelial cells (PECs) infiltrating cFSGS glomeruli. Transcripts for cathepsins B and C were increased in FSGS glomeruli compared with normal controls, and urinary excretion of both cathepsins was significantly greater in cFSGS compared with FSGS-NOS. Urinary excretion of ECM-derived peptides was enhanced in cFSGS, although in silico analysis did not identify enhanced excretion of peptides derived from cathepsin B or C | ||
| 520 | |a CONCLUSIONS: ECM differences suggest that glomerular sclerosis in cFSGS differs from that in other FSGS variants. Infiltration of activated PECs may disrupt ECM remodeling in cFSGS. These cells and their cathepsins may be therapeutic targets | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a cathepsin | |
| 650 | 4 | |a collapsing FSGS | |
| 650 | 4 | |a extracellular matrix | |
| 650 | 4 | |a focal segmental glomerulosclerosis | |
| 650 | 4 | |a glomerular epithelial cells | |
| 650 | 7 | |a Extracellular Matrix Proteins |2 NLM | |
| 650 | 7 | |a Cathepsins |2 NLM | |
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| 700 | 1 | |a Barati, Michelle T |e verfasserin |4 aut | |
| 700 | 1 | |a Caster, Dawn J |e verfasserin |4 aut | |
| 700 | 1 | |a Hata, Jessica L |e verfasserin |4 aut | |
| 700 | 1 | |a Hobeika, Liliane |e verfasserin |4 aut | |
| 700 | 1 | |a Coventry, Susan |e verfasserin |4 aut | |
| 700 | 1 | |a Brier, Michael E |e verfasserin |4 aut | |
| 700 | 1 | |a Wilkey, Daniel W |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Rood, Ilse M |e verfasserin |4 aut | |
| 700 | 1 | |a Deegens, Jeroen K |e verfasserin |4 aut | |
| 700 | 1 | |a Wetzels, Jack F |e verfasserin |4 aut | |
| 700 | 1 | |a Larsen, Christopher P |e verfasserin |4 aut | |
| 700 | 1 | |a Troost, Jonathan P |e verfasserin |4 aut | |
| 700 | 1 | |a Hodgin, Jeffrey B |e verfasserin |4 aut | |
| 700 | 1 | |a Mariani, Laura H |e verfasserin |4 aut | |
| 700 | 1 | |a Kretzler, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Klein, Jon B |e verfasserin |4 aut | |
| 700 | 1 | |a McLeish, Kenneth R |e verfasserin |4 aut | |
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