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Article: Anti-DNA antibody induction of protein kinase C phosphorylation and fibronectin synthesis in human and murine lupus and the effect of mycophenolic acid

TitleAnti-DNA antibody induction of protein kinase C phosphorylation and fibronectin synthesis in human and murine lupus and the effect of mycophenolic acid
Authors
Issue Date2009
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.interscience.wiley.com/jpages/0004-3591/
Citation
Arthritis And Rheumatism, 2009, v. 60 n. 7, p. 2071-2082 How to Cite?
AbstractObjective. To examine fibronectin (FN) expression in human lupus nephritis and the effect of anti-DNA antibodies on transforming growth factor β1 (TGFβ1) and FN synthesis in cultured human mesangial cells. The effects of mycophenolic acid (MPA) on this pathway, and the effects of mycophenolate mofetil (MMF) treatment in (NZB x NZW)F1/J mice were also studied. Methods. Immunohistochemical analyses of renal biopsy samples from patients with active diffuse proliferative lupus nephritis were performed. Cultured human mesangial cells were incubated with human polyclonal anti-DNA antibodies, with or without MPA. (NZB x NZW)F1/J mice with active nephritis were randomized to receive either MMF (100 mg/kg/day) or vehicle treatment for 12 weeks. Results. Glomerular FN expression was increased in patients with lupus nephritis, and it colocalized with IgG deposition. Anti-DNA antibodies induced protein kinase Cα (PKCα), PKCβI, and PKCβII activation, increased levels of bioactive TGFβ1, and increased FN synthesis in human mesangial cells (P < 0.001 for each comparison versus control conditions). Pretreatment of anti-DNA antibodies with exogenous DNA reduced their cellular binding and abrogated their induction of TGFβ1 and FN synthesis. Inhibition of PKC activation in human mesangial cells prior to anti-DNA antibody stimulation had no effect on cell proliferation, but resulted in significantly reduced antibody-mediated TGFβ1 secretion and FN synthesis. MPA treatment down-regulated PKCα, PKCβI, and PKCβII phosphorylation, reduced levels of TGFβ1 bioactivation, and decreased FN synthesis and deposition into the extracellular matrix. MMF treatment in (NZB + NZW)F1/J mice resulted in a reduction in glomerular IgG deposition, PKC activation, and FN expression, as well as an amelioration of proteinuria. Conclusion. Human polyclonal anti-DNA antibodies induce TGFβ1 and FN synthesis in human mesangial cells through PKC activation, which is inhibited by MPA. © 2009, American College of Rheumatology.
Persistent Identifierhttp://hdl.handle.net/10722/135250
ISSN
2015 Impact Factor: 8.955
2015 SCImago Journal Rankings: 3.206
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants Council General Research Fund7366/04M
University of Hong Kong Committee on Research and Conference10203731
University Grants Committee Matching Grant Scheme20700334
Funding Information:

Supported by the Hong Kong Research Grants Council General Research Fund (grant HKU 7366/04M), the University of Hong Kong Committee on Research and Conference Grants (grant 10203731), and the University Grants Committee Matching Grant Scheme (Phase II, grant 20700334). Dr. Yung's work was supported by the Endowment Fund of the Yu Professorship in Nephrology (awarded to Dr. Tak Mao Chan) and by the Wai Hung Charity Foundation.

References

 

DC FieldValueLanguage
dc.contributor.authorYung, Sen_HK
dc.contributor.authorZhang, Qen_HK
dc.contributor.authorChen, ZZen_HK
dc.contributor.authorKwok, WCen_HK
dc.contributor.authorSing, LLen_HK
dc.contributor.authorTak, MCen_HK
dc.date.accessioned2011-07-27T01:30:33Z-
dc.date.available2011-07-27T01:30:33Z-
dc.date.issued2009en_HK
dc.identifier.citationArthritis And Rheumatism, 2009, v. 60 n. 7, p. 2071-2082en_HK
dc.identifier.issn0004-3591en_HK
dc.identifier.urihttp://hdl.handle.net/10722/135250-
dc.description.abstractObjective. To examine fibronectin (FN) expression in human lupus nephritis and the effect of anti-DNA antibodies on transforming growth factor β1 (TGFβ1) and FN synthesis in cultured human mesangial cells. The effects of mycophenolic acid (MPA) on this pathway, and the effects of mycophenolate mofetil (MMF) treatment in (NZB x NZW)F1/J mice were also studied. Methods. Immunohistochemical analyses of renal biopsy samples from patients with active diffuse proliferative lupus nephritis were performed. Cultured human mesangial cells were incubated with human polyclonal anti-DNA antibodies, with or without MPA. (NZB x NZW)F1/J mice with active nephritis were randomized to receive either MMF (100 mg/kg/day) or vehicle treatment for 12 weeks. Results. Glomerular FN expression was increased in patients with lupus nephritis, and it colocalized with IgG deposition. Anti-DNA antibodies induced protein kinase Cα (PKCα), PKCβI, and PKCβII activation, increased levels of bioactive TGFβ1, and increased FN synthesis in human mesangial cells (P < 0.001 for each comparison versus control conditions). Pretreatment of anti-DNA antibodies with exogenous DNA reduced their cellular binding and abrogated their induction of TGFβ1 and FN synthesis. Inhibition of PKC activation in human mesangial cells prior to anti-DNA antibody stimulation had no effect on cell proliferation, but resulted in significantly reduced antibody-mediated TGFβ1 secretion and FN synthesis. MPA treatment down-regulated PKCα, PKCβI, and PKCβII phosphorylation, reduced levels of TGFβ1 bioactivation, and decreased FN synthesis and deposition into the extracellular matrix. MMF treatment in (NZB + NZW)F1/J mice resulted in a reduction in glomerular IgG deposition, PKC activation, and FN expression, as well as an amelioration of proteinuria. Conclusion. Human polyclonal anti-DNA antibodies induce TGFβ1 and FN synthesis in human mesangial cells through PKC activation, which is inhibited by MPA. © 2009, American College of Rheumatology.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.interscience.wiley.com/jpages/0004-3591/en_HK
dc.relation.ispartofArthritis and Rheumatismen_HK
dc.subject.meshAntibodies, Antinuclear - pharmacology-
dc.subject.meshEnzyme Inhibitors - pharmacology-
dc.subject.meshKidney - drug effects - metabolism - pathology-
dc.subject.meshLupus Nephritis - drug therapy - metabolism - pathology-
dc.subject.meshMycophenolic Acid - analogs and derivatives - pharmacology - therapeutic use-
dc.titleAnti-DNA antibody induction of protein kinase C phosphorylation and fibronectin synthesis in human and murine lupus and the effect of mycophenolic aciden_HK
dc.typeArticleen_HK
dc.identifier.emailYung, S:ssyyung@hku.hken_HK
dc.identifier.emailTak, MC:dtmchan@hku.hken_HK
dc.identifier.authorityYung, S=rp00455en_HK
dc.identifier.authorityTak, MC=rp00394en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1002/art.24573en_HK
dc.identifier.pmid19565476-
dc.identifier.scopuseid_2-s2.0-67650065024en_HK
dc.identifier.hkuros188580en_US
dc.identifier.hkuros157923-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-67650065024&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume60en_HK
dc.identifier.issue7en_HK
dc.identifier.spage2071en_HK
dc.identifier.epage2082en_HK
dc.identifier.eissn1529-0131-
dc.identifier.isiWOS:000267965900024-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYung, S=22636568800en_HK
dc.identifier.scopusauthoridZhang, Q=7406720527en_HK
dc.identifier.scopusauthoridChen, ZZ=35214246600en_HK
dc.identifier.scopusauthoridKwok, WC=24171150800en_HK
dc.identifier.scopusauthoridSing, LL=11641167800en_HK
dc.identifier.scopusauthoridTak, MC=7402687700en_HK

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