Glomerular clusterin is associated with PKC-α/β regulation and good outcome of membranous glomerulonephritis in humans

M. P. Rastaldi, G. Candiano, L. Musante, M. Bruschi, S. Armelloni, L. Rimoldi, R. Tardanico, S. Sanna Cherchi, F. Ferrario, V. Montinaro, R. Haupt, S. Parodi, M. L. Carnevali, L. Allegri, G. Camussi, L. Gesualdo, F. Scolari, G. M. Ghiggeri

Research output: Contribution to journalArticle

Abstract

Mechanisms for human membranous glomerulonepritis (MGN) remain elusive. Most up-to-date concepts still rely on the rat model of Passive Heymann Nephritis that derives from an autoimmune response to glomerular megalin, with complement activation and membrane attack complex assembly. Clusterin has been reported as a megalin ligand in immunodeposits, although its role has not been clarified. We studied renal biopsies of 60 MGN patients by immunohistochemistry utilizing antibodies against clusterin, C5b-9, and phosphorylated-protien kinase C (PKC) isoforms (pPKC). In vitro experiments were performed to investigate the role of clusterin during podocyte damage by MGN serum and define clusterin binding to human podocytes, where megalin is known to be absent. Clusterin, C5b-9, and pPKC-α/β showed highly variable glomerular staining, where high clusterin profiles were inversely correlated to C5b-9 and PKC-α/β expression (P=0.029), and co-localized with the low-density lipoprotein receptor (LDL-R). Glomerular clusterin emerged as the single factor influencing proteinuria at multivariate analysis and was associated with a reduction of proteinuria after a follow-up of 1.5 years (-88.1%, P=0.027). Incubation of podocytes with MGN sera determined strong upregulation of pPKC-α/β that was reverted by pre-incubation with clusterin, serum de-complementation, or protein-A treatment. Preliminary in vitro experiments showed podocyte binding of biotinilated clusterin, co-localization with LDL-R and specific binding inhibition with anti-LDL-R antibodies and with specific ligands. These data suggest a central role for glomerular clusterin in MGN as a modulator of inflammation that potentially influences the clinical outcome. Binding of clusterin to the LDL-R might offer an interpretative key for the pathogenesis of MGN in humans.

Original languageEnglish
Pages (from-to)477-485
Number of pages9
JournalKidney International
Volume70
Issue number3
DOIs
Publication statusPublished - Aug 21 2006

Fingerprint

Clusterin
Membranous Glomerulonephritis
Phosphotransferases
Complement Membrane Attack Complex
Podocytes
LDL Receptors
Low Density Lipoprotein Receptor-Related Protein-2
Proteinuria
Serum
Ligands
Antibodies
Complement Activation
Staphylococcal Protein A
Autoimmunity
Protein Isoforms
Up-Regulation
Multivariate Analysis

Keywords

  • Clusterin
  • Membranous glomerulonephritis
  • Nephrotic syndrome
  • PKC

ASJC Scopus subject areas

  • Nephrology

Cite this

Glomerular clusterin is associated with PKC-α/β regulation and good outcome of membranous glomerulonephritis in humans. / Rastaldi, M. P.; Candiano, G.; Musante, L.; Bruschi, M.; Armelloni, S.; Rimoldi, L.; Tardanico, R.; Cherchi, S. Sanna; Ferrario, F.; Montinaro, V.; Haupt, R.; Parodi, S.; Carnevali, M. L.; Allegri, L.; Camussi, G.; Gesualdo, L.; Scolari, F.; Ghiggeri, G. M.

In: Kidney International, Vol. 70, No. 3, 21.08.2006, p. 477-485.

Research output: Contribution to journalArticle

Rastaldi, MP, Candiano, G, Musante, L, Bruschi, M, Armelloni, S, Rimoldi, L, Tardanico, R, Cherchi, SS, Ferrario, F, Montinaro, V, Haupt, R, Parodi, S, Carnevali, ML, Allegri, L, Camussi, G, Gesualdo, L, Scolari, F & Ghiggeri, GM 2006, 'Glomerular clusterin is associated with PKC-α/β regulation and good outcome of membranous glomerulonephritis in humans', Kidney International, vol. 70, no. 3, pp. 477-485. https://doi.org/10.1038/sj.ki.5001563
Rastaldi, M. P. ; Candiano, G. ; Musante, L. ; Bruschi, M. ; Armelloni, S. ; Rimoldi, L. ; Tardanico, R. ; Cherchi, S. Sanna ; Ferrario, F. ; Montinaro, V. ; Haupt, R. ; Parodi, S. ; Carnevali, M. L. ; Allegri, L. ; Camussi, G. ; Gesualdo, L. ; Scolari, F. ; Ghiggeri, G. M. / Glomerular clusterin is associated with PKC-α/β regulation and good outcome of membranous glomerulonephritis in humans. In: Kidney International. 2006 ; Vol. 70, No. 3. pp. 477-485.
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AU - Candiano, G.

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AU - Bruschi, M.

AU - Armelloni, S.

AU - Rimoldi, L.

AU - Tardanico, R.

AU - Cherchi, S. Sanna

AU - Ferrario, F.

AU - Montinaro, V.

AU - Haupt, R.

AU - Parodi, S.

AU - Carnevali, M. L.

AU - Allegri, L.

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AU - Gesualdo, L.

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AU - Ghiggeri, G. M.

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N2 - Mechanisms for human membranous glomerulonepritis (MGN) remain elusive. Most up-to-date concepts still rely on the rat model of Passive Heymann Nephritis that derives from an autoimmune response to glomerular megalin, with complement activation and membrane attack complex assembly. Clusterin has been reported as a megalin ligand in immunodeposits, although its role has not been clarified. We studied renal biopsies of 60 MGN patients by immunohistochemistry utilizing antibodies against clusterin, C5b-9, and phosphorylated-protien kinase C (PKC) isoforms (pPKC). In vitro experiments were performed to investigate the role of clusterin during podocyte damage by MGN serum and define clusterin binding to human podocytes, where megalin is known to be absent. Clusterin, C5b-9, and pPKC-α/β showed highly variable glomerular staining, where high clusterin profiles were inversely correlated to C5b-9 and PKC-α/β expression (P=0.029), and co-localized with the low-density lipoprotein receptor (LDL-R). Glomerular clusterin emerged as the single factor influencing proteinuria at multivariate analysis and was associated with a reduction of proteinuria after a follow-up of 1.5 years (-88.1%, P=0.027). Incubation of podocytes with MGN sera determined strong upregulation of pPKC-α/β that was reverted by pre-incubation with clusterin, serum de-complementation, or protein-A treatment. Preliminary in vitro experiments showed podocyte binding of biotinilated clusterin, co-localization with LDL-R and specific binding inhibition with anti-LDL-R antibodies and with specific ligands. These data suggest a central role for glomerular clusterin in MGN as a modulator of inflammation that potentially influences the clinical outcome. Binding of clusterin to the LDL-R might offer an interpretative key for the pathogenesis of MGN in humans.

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