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Abstract: PO2441

Parenteral Iron Therapy Alters Polarization of Kidney Macrophages and Mitigates Kidney Fibrosis in Mice

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Patino, Edwin, Weill Cornell Medicine, New York, New York, United States
  • Bhatia, Divya, Weill Cornell Medicine, New York, New York, United States
  • Vance, Steven Zebulon, New York Blood Center, New York, New York, United States
  • Vinchi, Francesca, New York Blood Center, New York, New York, United States
  • Rivella, Stefano, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Choi, Mary E., Weill Cornell Medicine, New York, New York, United States
  • Akchurin, Oleh M., Weill Cornell Medicine, New York, New York, United States
Background

Iron therapy is common in patients with chronic kidney disease (CKD). Macrophages are a major cell type capable of handling and storing iron. At the same time, macrophages play a critical role in the pathogenesis of kidney fibrosis. Iron has been shown to modulate macrophage polarization in other pathologic conditions. However, the effect of iron therapy on polarization of kidney macrophages during kidney fibrosis is unclear.

Methods

To elucidate this, we took advantage of two mouse models of kidney fibrosis: adenine and the unilateral ureteral obstruction (UUO) models. A subset of mice received weekly intraperitoneal injections of iron dextran (0.5 g/kg body weight) in addition to adenine. Same iron administration regimen was used to treat a sub-group of mice for 4 weeks prior to UUO. Mice were euthanized after 8 weeks of adenine diet or 7 days after UUO. Blood for serum creatinine and CBC measurements and kidneys were collected at euthanasia.

Results

Iron therapy improved anemia and mitigated kidney function decline in CKD mice, as indicated by serum creatinine improvement. Kidney fibrosis was less severe in mice treated with iron compared to untreated mice in both the adenine and UUO models, as indicated by Masson trichrome staining and reduced kidney expression of fibronectin. Prussian blue staining identified iron accumulation in the kidney interstitium of CKD mice treated with iron, specifically within kidney macrophages, as confirmed by electron microscopy. Flow cytometry demonstrated reduced infiltration of kidney tissue by Ly6Chigh monocytes and neutrophils and lower percentage of kidney CCR2+ and CX3CR1+ myeloid cells in CKD mice treated with iron compared to untreated CKD mice. While macrophage surface markers MHCII, CD86, and CD206 were altered by iron therapy, they did not follow the classical M1/M2 dichotomy. However, expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β by kidney macrophages was reduced in CKD mice treated with iron compared to untreated CKD mice.

Conclusion

Chronic parenteral administration of iron mitigated kidney fibrosis in two different mouse models, which, at least in part, was likely mediated by iron-induced kidney macrophage skewing towards an anti-inflammatory phenotype and reduced recruitment of pro-inflammatory cells into the kidney.

Funding

  • NIDDK Support