Therapeutic Benefit of Regulating Iron Metabolism in Spontaneous Lupus Nephritis

Abstract

Background Lupus nephritis (LN) is an end-organ complication of Systemic lupus erythematosus and is more common in premenopausal women. Hepcidin, the master regulator of iron homeostasis, modulates inflammation and is negatively regulated by estrogen. Therefore, we hypothesized that exogenous hepcidin may reduce the severity and delay the onset of LN. Methods Pre-nephritic 8-week-old or nephritic 16-week-old MRL/lpr female mice were injected Hepcidin (50ug, i.p) or vehicle twice a week and markers of renal injury and inflammation were examined at 18 and 20 weeks of age. The direct effect of hepcidin on macrophages was studied in-vitro. Results Hepcidin reduced intrarenal iron accumulation, and increased H-ferritin. This was associated with reduced renal inflammation and immune cell infiltration, which collectively mitigated microalbuminuria and tubular injury, independent of immune complex deposits and autoantibodies. The increase in H-ferritin, was associated with a reduced number of renal Ki-67+-F4/80+ macrophages. In-vitro, hepcidin induced H-ferritin in macrophages and reduced labile (Fe2+) iron. H-ferritinhi macrophages proliferated less upon Mcsf-1 stimulation and secreted less IL-1b, and IL-6 upon TLR-3 activation. Hepcidin reduced microalbuminuria when administered to nephritic, 16-week-old mice without worsening lupus-associated anemia. Conclusions We have identified that hepcidin targets iron homeostasis and reduces cardinal pathogenic features of LN. Importantly, Hepcidin treatment ameliorates kidney disease in mice with established proteinuria. Thus, our data highlight that targeting cellular iron metabolism with hepcidin represents a promising and a new therapeutic strategy in LN.