Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis
Autor(a) principal: | |
---|---|
Data de Publicação: | 2012 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/34710 http://dx.doi.org/10.1371/journal.pone.0032454 |
Resumo: | A growing body of evidence demonstrates a correlation between Th2 cytokines and the development of focal and segmental glomerulosclerosis ( FSGS). Therefore, we hypothesized that GSL-1, a monoglycosylceramide from Sphingomonas ssp. with pro-Th1 activity on invariant Natural Killer T ( iNKT) lymphocytes, could counterbalance the Th2 profile and modulate glomerulosclerosis. Using an adriamycin( ADM)-based model of FSGS, we found that BALB/c mice presented albuminuria and glomerular degeneration in association with a Th2-like pro-fibrogenic profile; these mice also expressed a combination of inflammatory cytokines, such as IL-4, IL-1 alpha, IL-1 beta, IL-17, TNF-alpha, and chemokines, such as RANTES and eotaxin. in addition, we observed a decrease in the mRNA levels of GD3 synthase, the enzyme responsible for GD3 metabolism, a glycolipid associated with podocyte physiology. GSL-1 treatment inhibited ADM-induced renal dysfunction and preserved kidney architecture, a phenomenon associated with the induction of a Th1-like response, increased levels of GD3 synthase transcripts and inhibition of pro-fibrotic transcripts and inflammatory cytokines. TGF-beta analysis revealed increased levels of circulating protein and tissue transcripts in both ADM- and GSL-1-treated mice, suggesting that TGF-beta could be associated with both FSGS pathology and iNKT-mediated immunosuppression; therefore, we analyzed the kidney expression of phosphorylated SMAD2/3 and SMAD7 proteins, molecules associated with the deleterious and protective effects of TGF-beta, respectively. We found high levels of phosphoSMAD2/3 in ADM mice in contrast to the GSL-1 treated group in which SMAD7 expression increased. These data suggest that GSL-1 treatment modulates the downstream signaling of TGF-beta through a renoprotective pathway. Finally, GSL-1 treatment at day 4, a period when proteinuria was already established, was still able to improve renal function, preserve renal structure and inhibit fibrogenic transcripts. in conclusion, our work demonstrates that the iNKT agonist GSL-1 modulates the pathogenesis of ADM-induced glomerulosclerosis and may provide an alternative approach to disease management. |
id |
UFSP_d18064a13de9bcf21d6c46cdcc57c80a |
---|---|
oai_identifier_str |
oai:repositorio.unifesp.br:11600/34710 |
network_acronym_str |
UFSP |
network_name_str |
Repositório Institucional da UNIFESP |
repository_id_str |
3465 |
spelling |
Pereira, Rafael L. [UNIFESP]Reis, Vanessa O. [UNIFESP]Semedo, Patricia [UNIFESP]Buscariollo, Bruna N. [UNIFESP]Donizetti-Oliveira, Cassiano [UNIFESP]Cenedeze, Marcos Antonio [UNIFESP]Soares, Maria Fernanda Sanches [UNIFESP]Pacheco-Silva, Alvaro [UNIFESP]Savage, Paul B.Câmara, Niels Olsen Saraiva [UNIFESP]Keller, Alexandre C. [UNIFESP]Universidade Federal de São Paulo (UNIFESP)Inst Israelita Ensino & Pesquisa Albert EinsteinBrigham Young UnivUniversidade de São Paulo (USP)2016-01-24T14:26:58Z2016-01-24T14:26:58Z2012-03-12Plos One. San Francisco: Public Library Science, v. 7, n. 3, 11 p., 2012.1932-6203http://repositorio.unifesp.br/handle/11600/34710http://dx.doi.org/10.1371/journal.pone.0032454WOS000302381500017.pdf10.1371/journal.pone.0032454WOS:000302381500017A growing body of evidence demonstrates a correlation between Th2 cytokines and the development of focal and segmental glomerulosclerosis ( FSGS). Therefore, we hypothesized that GSL-1, a monoglycosylceramide from Sphingomonas ssp. with pro-Th1 activity on invariant Natural Killer T ( iNKT) lymphocytes, could counterbalance the Th2 profile and modulate glomerulosclerosis. Using an adriamycin( ADM)-based model of FSGS, we found that BALB/c mice presented albuminuria and glomerular degeneration in association with a Th2-like pro-fibrogenic profile; these mice also expressed a combination of inflammatory cytokines, such as IL-4, IL-1 alpha, IL-1 beta, IL-17, TNF-alpha, and chemokines, such as RANTES and eotaxin. in addition, we observed a decrease in the mRNA levels of GD3 synthase, the enzyme responsible for GD3 metabolism, a glycolipid associated with podocyte physiology. GSL-1 treatment inhibited ADM-induced renal dysfunction and preserved kidney architecture, a phenomenon associated with the induction of a Th1-like response, increased levels of GD3 synthase transcripts and inhibition of pro-fibrotic transcripts and inflammatory cytokines. TGF-beta analysis revealed increased levels of circulating protein and tissue transcripts in both ADM- and GSL-1-treated mice, suggesting that TGF-beta could be associated with both FSGS pathology and iNKT-mediated immunosuppression; therefore, we analyzed the kidney expression of phosphorylated SMAD2/3 and SMAD7 proteins, molecules associated with the deleterious and protective effects of TGF-beta, respectively. We found high levels of phosphoSMAD2/3 in ADM mice in contrast to the GSL-1 treated group in which SMAD7 expression increased. These data suggest that GSL-1 treatment modulates the downstream signaling of TGF-beta through a renoprotective pathway. Finally, GSL-1 treatment at day 4, a period when proteinuria was already established, was still able to improve renal function, preserve renal structure and inhibit fibrogenic transcripts. in conclusion, our work demonstrates that the iNKT agonist GSL-1 modulates the pathogenesis of ADM-induced glomerulosclerosis and may provide an alternative approach to disease management.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientificoe Tecnologico, BrazilUniversidade Federal de São Paulo, Dept Med Nefrol, São Paulo, BrazilInst Israelita Ensino & Pesquisa Albert Einstein, Unidade Transplante Renal, São Paulo, BrazilBrigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USAUniv São Paulo, Dept Imunol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Imunol & Parasitol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med Nefrol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Imunol & Parasitol, São Paulo, BrazilFAPESP: 2007/07120-0Conselho Nacional de Desenvolvimento Cientificoe Tecnologico, Brazil: 501848/2009-6Conselho Nacional de Desenvolvimento Cientificoe Tecnologico, Brazil: 484445/2010-3Web of Science11engPublic Library SciencePlos OneInvariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosisinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP11600/347102022-11-04 15:31:40.522metadata only accessoai:repositorio.unifesp.br:11600/34710Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652022-11-04T18:31:40Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis |
title |
Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis |
spellingShingle |
Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis Pereira, Rafael L. [UNIFESP] |
title_short |
Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis |
title_full |
Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis |
title_fullStr |
Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis |
title_full_unstemmed |
Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis |
title_sort |
Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis |
author |
Pereira, Rafael L. [UNIFESP] |
author_facet |
Pereira, Rafael L. [UNIFESP] Reis, Vanessa O. [UNIFESP] Semedo, Patricia [UNIFESP] Buscariollo, Bruna N. [UNIFESP] Donizetti-Oliveira, Cassiano [UNIFESP] Cenedeze, Marcos Antonio [UNIFESP] Soares, Maria Fernanda Sanches [UNIFESP] Pacheco-Silva, Alvaro [UNIFESP] Savage, Paul B. Câmara, Niels Olsen Saraiva [UNIFESP] Keller, Alexandre C. [UNIFESP] |
author_role |
author |
author2 |
Reis, Vanessa O. [UNIFESP] Semedo, Patricia [UNIFESP] Buscariollo, Bruna N. [UNIFESP] Donizetti-Oliveira, Cassiano [UNIFESP] Cenedeze, Marcos Antonio [UNIFESP] Soares, Maria Fernanda Sanches [UNIFESP] Pacheco-Silva, Alvaro [UNIFESP] Savage, Paul B. Câmara, Niels Olsen Saraiva [UNIFESP] Keller, Alexandre C. [UNIFESP] |
author2_role |
author author author author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Universidade Federal de São Paulo (UNIFESP) Inst Israelita Ensino & Pesquisa Albert Einstein Brigham Young Univ Universidade de São Paulo (USP) |
dc.contributor.author.fl_str_mv |
Pereira, Rafael L. [UNIFESP] Reis, Vanessa O. [UNIFESP] Semedo, Patricia [UNIFESP] Buscariollo, Bruna N. [UNIFESP] Donizetti-Oliveira, Cassiano [UNIFESP] Cenedeze, Marcos Antonio [UNIFESP] Soares, Maria Fernanda Sanches [UNIFESP] Pacheco-Silva, Alvaro [UNIFESP] Savage, Paul B. Câmara, Niels Olsen Saraiva [UNIFESP] Keller, Alexandre C. [UNIFESP] |
description |
A growing body of evidence demonstrates a correlation between Th2 cytokines and the development of focal and segmental glomerulosclerosis ( FSGS). Therefore, we hypothesized that GSL-1, a monoglycosylceramide from Sphingomonas ssp. with pro-Th1 activity on invariant Natural Killer T ( iNKT) lymphocytes, could counterbalance the Th2 profile and modulate glomerulosclerosis. Using an adriamycin( ADM)-based model of FSGS, we found that BALB/c mice presented albuminuria and glomerular degeneration in association with a Th2-like pro-fibrogenic profile; these mice also expressed a combination of inflammatory cytokines, such as IL-4, IL-1 alpha, IL-1 beta, IL-17, TNF-alpha, and chemokines, such as RANTES and eotaxin. in addition, we observed a decrease in the mRNA levels of GD3 synthase, the enzyme responsible for GD3 metabolism, a glycolipid associated with podocyte physiology. GSL-1 treatment inhibited ADM-induced renal dysfunction and preserved kidney architecture, a phenomenon associated with the induction of a Th1-like response, increased levels of GD3 synthase transcripts and inhibition of pro-fibrotic transcripts and inflammatory cytokines. TGF-beta analysis revealed increased levels of circulating protein and tissue transcripts in both ADM- and GSL-1-treated mice, suggesting that TGF-beta could be associated with both FSGS pathology and iNKT-mediated immunosuppression; therefore, we analyzed the kidney expression of phosphorylated SMAD2/3 and SMAD7 proteins, molecules associated with the deleterious and protective effects of TGF-beta, respectively. We found high levels of phosphoSMAD2/3 in ADM mice in contrast to the GSL-1 treated group in which SMAD7 expression increased. These data suggest that GSL-1 treatment modulates the downstream signaling of TGF-beta through a renoprotective pathway. Finally, GSL-1 treatment at day 4, a period when proteinuria was already established, was still able to improve renal function, preserve renal structure and inhibit fibrogenic transcripts. in conclusion, our work demonstrates that the iNKT agonist GSL-1 modulates the pathogenesis of ADM-induced glomerulosclerosis and may provide an alternative approach to disease management. |
publishDate |
2012 |
dc.date.issued.fl_str_mv |
2012-03-12 |
dc.date.accessioned.fl_str_mv |
2016-01-24T14:26:58Z |
dc.date.available.fl_str_mv |
2016-01-24T14:26:58Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Plos One. San Francisco: Public Library Science, v. 7, n. 3, 11 p., 2012. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/34710 http://dx.doi.org/10.1371/journal.pone.0032454 |
dc.identifier.issn.none.fl_str_mv |
1932-6203 |
dc.identifier.file.none.fl_str_mv |
WOS000302381500017.pdf |
dc.identifier.doi.none.fl_str_mv |
10.1371/journal.pone.0032454 |
dc.identifier.wos.none.fl_str_mv |
WOS:000302381500017 |
identifier_str_mv |
Plos One. San Francisco: Public Library Science, v. 7, n. 3, 11 p., 2012. 1932-6203 WOS000302381500017.pdf 10.1371/journal.pone.0032454 WOS:000302381500017 |
url |
http://repositorio.unifesp.br/handle/11600/34710 http://dx.doi.org/10.1371/journal.pone.0032454 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.none.fl_str_mv |
Plos One |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
11 |
dc.publisher.none.fl_str_mv |
Public Library Science |
publisher.none.fl_str_mv |
Public Library Science |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UNIFESP instname:Universidade Federal de São Paulo (UNIFESP) instacron:UNIFESP |
instname_str |
Universidade Federal de São Paulo (UNIFESP) |
instacron_str |
UNIFESP |
institution |
UNIFESP |
reponame_str |
Repositório Institucional da UNIFESP |
collection |
Repositório Institucional da UNIFESP |
repository.name.fl_str_mv |
Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP) |
repository.mail.fl_str_mv |
|
_version_ |
1802764185744965632 |