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Title: Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis
Authors: 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 Einstein
Brigham Young Univ
Universidade de São Paulo (USP)
Issue Date: 12-Mar-2012
Publisher: Public Library Science
Citation: Plos One. San Francisco: Public Library Science, v. 7, n. 3, 11 p., 2012.
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.
ISSN: 1932-6203
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