Abstract: SA-PO327

Role of Hepcidin and Iron Homeostasis in the Progression of AKI to CKD

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Mandziak, Ewa U., University of Virginia, Charlottesville, Virginia, United States
  • Scindia, Yogesh M., Univerisity of Virginia, Charlottesville, Virginia, United States
  • Loi, Valentina, AO Brotzu Cagliari, Cagliari, Italy
  • Mohammad, Saleh, University of Virginia, Charlottesville, Virginia, United States
  • Swaminathan, Sundararaman, University of Virginia, Charlottesville, Virginia, United States
Background

Maladaptive repair and fibrosis after acute kidney injury (AKI) contributes to progressive loss of kidney function. Systemic iron depletion strategies using iron chelators or diet-induced iron deficiency are known to reduce renal fibrosis. Splenic red pulp macrophages are one of the primary storage sites for iron. Hepcidin (Hamp), the master regulator of iron homeostasis, plays an important role in anemia of chronic kidney disease (CKD) through its effects on hepatic and splenic macrophages. We hypothesized that hepcidin dependent changes in systemic iron homeostasis may modulate renal fibrosis.

Methods

To induce CKD, Folic Acid (FA) 250 mg/kg (i.p.) was administered to WT, Hamp KO and Hamp Het mice (all on C57BL/6J background). BUN was measured to monitor AKI on day 2. In some experiments Hamp Het mice were reconstituted with exogenous hepcidin (50 µg, i.p) after the onset of AKI. Renal function and fibrosis related parameters were examined 19 days later.

Results

Compared to WT mice, AKI and mortality were reduced in Hamp het and Hamp KO mice. This initial worse AKI translated to more severe fibrosis on day 19 in WT, as indicated by collagen and α smooth muscle actin content. Both these parameters were significantly lower in Hamp deficient mice. There was a large infiltration of F4/80+ macrophages in the fibrotic kidneys of the WT and Hamp KO mice, that was not seen in Hamp Het mice. Compared to WT kidneys, there was a significant reduction in both NOS-2 and Arginase-1 gene expression in Hamp Het kidneys. Arginase-1 showed a downward trend in Hamp KO kidneys also. Hepcidin reconstitution exacerbated renal fibrosis in Hamp Het mice.

Conclusion

Our studies reveal a novel protective role of hepcidin deficiency in progression of AKI to CKD. This protection was associated with reduction in splenic iron content and renal M2 macrophage infiltration.

Funding

  • NIDDK Support