title: Invariant natural killer T cell agonist modulates experimental focal and segmental glomerulosclerosis.
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-1α, IL-1β, IL-17, TNF-α, 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-β analysis revealed increased levels of circulating protein and tissue transcripts in both ADM- and GSL-1-treated mice, suggesting that TGF-β 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-β, 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-β 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.
authors.affiliation: Departamento de Medicina - Nefrologia, Universidade Federal de São Paulo, São Paulo, Brasil.
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Pereira
authors.forename: Vanessa O
authors.initials: VO
authors.lastname: Reis
authors.forename: Patricia
authors.initials: P
authors.lastname: Semedo
authors.forename: Bruna N
authors.initials: BN
authors.lastname: Buscariollo
authors.forename: Cassiano
authors.initials: C
authors.lastname: Donizetti-Oliveira
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Cenedeze
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Soares
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pacheco-Silva
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.forename: Niels O S
authors.initials: NO
authors.lastname: Câmara
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Keller
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002518:Ceramides / Q000494:pharmacology*; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D004317:Doxorubicin / Q000633:toxicity; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012799:Sialyltransferases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism; D020578:Sphingomonas / Q000737:chemistry*; D018418:Th2 Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D002518:Ceramides; D018925:Chemokines; D016207:Cytokines; D017931:DNA Primers; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D004317:Doxorubicin; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase