Kidney Week

Abstract: TH-PO827

Hepcidin Modulates Macrophage Iron Metabolism to Attenuate Lupus Nephritis

Session Information

• Glomerular Diseases: Immunology and Inflammation - I
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Scindia, Yogesh M., University of Virginia, Charlottesville, Virginia, United States

Yogesh M. Scindia,

• Mandziak, Ewa U., University of Virginia, Charlottesville, Virginia, United States

Ewa U. Mandziak,

• Loi, Valentina, AO Brotzu Cagliari, Cagliari, Italy

Valentina Loi,

• Leeds, Joseph T., University of Virginia, Charlottesville, Virginia, United States

Joseph T. Leeds,

• Swaminathan, Sundararaman, University of Virginia, Charlottesville, Virginia, United States

Sundararaman Swaminathan,

Background

Lupus nephritis (LN) is an end-organ manifestation of systemic lupus erythematosus (SLE) mostly affecting the female population. Renal inflammation, macrophage recruitment and proliferation are associated with worse outcome in LN. Hepcidin is a primary regulatory of macrophage iron metabolism and phenotype. The role of Hepcidin or iron transport has not been investigated in lupus.We hypothesized that hepcidin would mitigate LN by targeting macrophage responses.

Methods

8-week-old femaleMRL/lpr mice (a spontaneous model of SLE) were treated twice a week with saline or 50 μg of hepcidin (i.p) for 10 weeks, following which outcomes like microalbuminuria, histopathology, and other markers of macrophage inflammation and proliferation were examined. In-vitro, macrophages (J774A) were treated with Hepcidin and stimulated with Polyinosinic-polycytidylic acid (Poly (I:C)) or M-CSF1 to evaluate inflammatory and proliferative response.

Results

Saline-treated mice developed severe LN by 18 weeks of age as indicated by high microalbuminuria, fibrosis, renal Cox-2, IL-6, CXCL-1 and M-CSF transcripts, immune complex deposits, iron accumulation and an infiltration of F4/80+ve macrophages. Hepcidin treatment significantly reduced all these manifestations of LN. There was an increase in renal H-ferritin and a concomitant decrease Rrm-1 and Rrm-2, iron dependent enzymes required for DNA synthesis. This was associated with a reduction in Ki-67 positive macrophages and other cells within the kidney. In-vitro hepcidin induced H-ferritin in macrophages and reduced their labile iron (Fe²⁺) content. H-ferritin^himacrophages secreted less IL-1bfollowing Poly (I:C) stimulation and proliferated less in response to M-CSF1.

Conclusion

We demonstrate a novel protective effect of hepcidinagainst LN which could open new therapeutic approaches to treat LN. Hepcidin induces H-ferritin that lowers labile iron and reduces inflammatory response and macrophage proliferation, two cardinal features of LN. Renal iron accumulation and increased Cox-2 suggest involvement of Ferroptosis in the pathogenesis of SLE. Further studies are required to investigate whether hepcidin also targets renal parenchymal cells or other immune effectors.

Funding

• NIDDK Support