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.

Administration of α-Galactosylceramide Improves Adenine-Induced Renal Injury

“…In experimental models of lung diseases, Kimura et al (34) observed that the administration of αGalCer increased survival and reduced pulmonary fibrosis and TGF-β levels in the bleomycin model. In renal diseases, Pereira et al (35) found that GSL-1 (another NKT agonist) modulates the development of experimental focal and segmental glomerulosclerosis (EFSG) and, in the study by Mesnard et al (36), Jα18KO mice demonstrated worse renal function in anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These data support our findings that Jα18 knockout mice are prone to a higher percentage of fibrosis and that administration of αGalCer was effective in reducing this process.…”

The balance of kinin receptors in the progression of experimental focal and segmental glomerulosclerosis

“…In the balb/c mouse background, a 10 mg/kg dose of ADM was injected to induce the disease (Pereira et al, 2011; Pereira et al, 2012). In the C57black/6 strain, a higher dose of 25 mg/kg ADM was used (Jeansson et al, 2009).…”

Significance of the urokinase-type plasminogen activator and its receptor in the progression of focal segmental glomerulosclerosis in clinical and mouse models

“…The immunological mechanisms involved in the pathogenesis of FSGS are unclear, but evidence suggests an association between Th2-polarization and disease development [ 50 ]. For example, Yap et al reported a correlation between childhood idiopathic nephrotic syndrome and increased IL-13 mRNA expression.…”