Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis

Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis

Author Pereira, Rafael L. Autor UNIFESP Google Scholar
Reis, Vanessa O. Autor UNIFESP Google Scholar
Semedo, Patricia Autor UNIFESP Google Scholar
Buscariollo, Bruna N. Autor UNIFESP Google Scholar
Donizetti-Oliveira, Cassiano Autor UNIFESP Google Scholar
Cenedeze, Marcos Antonio Autor UNIFESP Google Scholar
Soares, Maria Fernanda Sanches Autor UNIFESP Google Scholar
Pacheco-Silva, Alvaro Autor UNIFESP Google Scholar
Savage, Paul B. Google Scholar
Câmara, Niels Olsen Saraiva Autor UNIFESP Google Scholar
Keller, Alexandre C. Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Inst Israelita Ensino & Pesquisa Albert Einstein
Brigham Young Univ
Universidade de São Paulo (USP)
Abstract 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.
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Cientificoe Tecnologico, Brazil
Grant number FAPESP: 2007/07120-0
Conselho Nacional de Desenvolvimento Cientificoe Tecnologico, Brazil: 501848/2009-6
Conselho Nacional de Desenvolvimento Cientificoe Tecnologico, Brazil: 484445/2010-3
Date 2012-03-12
Published in Plos One. San Francisco: Public Library Science, v. 7, n. 3, 11 p., 2012.
ISSN 1932-6203 (Sherpa/Romeo, impact factor)
Publisher Public Library Science
Extent 11
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000302381500017

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