Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a likely antigenic target in membranous nephropathy and nonsteroidal anti-inflammatory drug use
Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved..
Drugs are an important secondary cause of membranous nephropathy (MN) with the most common drugs associated with MN being nonsteroidal anti-inflammatory drugs (NSAIDs). Since the target antigen in NSAID-associated MN is not known, we performed laser microdissection of glomeruli followed by mass spectrometry (MS/MS) in 250 cases of PLA2R-negative MN to identify novel antigenic targets. This was followed by immunohistochemistry to localize the target antigen along the glomerular basement membrane and western blot analyses of eluates of frozen biopsy tissue to detect binding of IgG to the novel antigenic target. MS/MS studies revealed high total spectral counts of a novel protein Proprotein Convertase Subtilisin/Kexin Type 6 (PCSK 6) in five of the 250 cases in the discovery cohort. A validation cohort using protein G immunoprecipitation, MS/MS, and immunofluorescence detected PCSK6 in eight additional cases. All cases were negative for known antigens. Ten of 13 cases had a history of heavy NSAID use with no history available in one case. The mean serum creatinine and proteinuria at kidney biopsy were 0.93 ± 0.47 mg/dL and 6.5 ± 3.3 gms/day, respectively. Immunohistochemistry/immunofluorescence showed granular staining for PCSK6 along the glomerular basement membrane, and confocal microscopy showed co-localization of IgG and PCSK6. IgG subclass analysis in three cases revealed codominance of IgG1 and IgG4. Western blot analysis using eluates from frozen tissue showed IgG binding to PCSK6 in PCSK6-associated but not in PLA2R-positive MN. Thus, PCSK6 may be a likely novel antigenic target in MN in patients with prolonged NSAID use.
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CommentIn: Kidney Int. 2023 Aug;104(2):242-244. - PMID 37479386 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:104 |
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| Enthalten in: |
Kidney international - 104(2023), 2 vom: 27. Aug., Seite 343-352 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sethi, Sanjeev [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.07.2023 Date Revised 25.10.2023 published: Print-Electronic CommentIn: Kidney Int. 2023 Aug;104(2):242-244. - PMID 37479386 Citation Status MEDLINE |
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| doi: |
10.1016/j.kint.2023.04.006 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM356232700 |
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| 245 | 1 | 0 | |a Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a likely antigenic target in membranous nephropathy and nonsteroidal anti-inflammatory drug use |
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| 500 | |a Date Completed 24.07.2023 | ||
| 500 | |a Date Revised 25.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Kidney Int. 2023 Aug;104(2):242-244. - PMID 37479386 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Drugs are an important secondary cause of membranous nephropathy (MN) with the most common drugs associated with MN being nonsteroidal anti-inflammatory drugs (NSAIDs). Since the target antigen in NSAID-associated MN is not known, we performed laser microdissection of glomeruli followed by mass spectrometry (MS/MS) in 250 cases of PLA2R-negative MN to identify novel antigenic targets. This was followed by immunohistochemistry to localize the target antigen along the glomerular basement membrane and western blot analyses of eluates of frozen biopsy tissue to detect binding of IgG to the novel antigenic target. MS/MS studies revealed high total spectral counts of a novel protein Proprotein Convertase Subtilisin/Kexin Type 6 (PCSK 6) in five of the 250 cases in the discovery cohort. A validation cohort using protein G immunoprecipitation, MS/MS, and immunofluorescence detected PCSK6 in eight additional cases. All cases were negative for known antigens. Ten of 13 cases had a history of heavy NSAID use with no history available in one case. The mean serum creatinine and proteinuria at kidney biopsy were 0.93 ± 0.47 mg/dL and 6.5 ± 3.3 gms/day, respectively. Immunohistochemistry/immunofluorescence showed granular staining for PCSK6 along the glomerular basement membrane, and confocal microscopy showed co-localization of IgG and PCSK6. IgG subclass analysis in three cases revealed codominance of IgG1 and IgG4. Western blot analysis using eluates from frozen tissue showed IgG binding to PCSK6 in PCSK6-associated but not in PLA2R-positive MN. Thus, PCSK6 may be a likely novel antigenic target in MN in patients with prolonged NSAID use | ||
| 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 NSAID | |
| 650 | 4 | |a PCSK6 | |
| 650 | 4 | |a membranous nephropathy | |
| 650 | 4 | |a proteomics | |
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| 650 | 7 | |a Serine Endopeptidases |2 NLM | |
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| 700 | 1 | |a Casal Moura, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Madden, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Debiec, Hanna |e verfasserin |4 aut | |
| 700 | 1 | |a Nasr, Samih H |e verfasserin |4 aut | |
| 700 | 1 | |a Larsen, Christopher P |e verfasserin |4 aut | |
| 700 | 1 | |a Gross, LouAnn |e verfasserin |4 aut | |
| 700 | 1 | |a Negron, Vivian |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Raman Deep |e verfasserin |4 aut | |
| 700 | 1 | |a Nath, Karl A |e verfasserin |4 aut | |
| 700 | 1 | |a Storey, Aaron J |e verfasserin |4 aut | |
| 700 | 1 | |a Specks, Ulrich |e verfasserin |4 aut | |
| 700 | 1 | |a Fervenza, Fernando C |e verfasserin |4 aut | |
| 700 | 1 | |a Ronco, Pierre |e verfasserin |4 aut | |
| 700 | 1 | |a Caza, Tiffany N |e verfasserin |4 aut | |
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