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Abstract: FR-OR102

Impaired Renal Iron Handling Leads to Iron Overload through an ET-1 Dependent Pathway

Session Information

Category: Anemia and Iron Metabolism

  • 201 Anemia and Iron Metabolism: Basic

Authors

  • Kasztan, Malgorzata, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Hyndman, Kelly A., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Pollock, David M., University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Elevated plasma endothelin-1 (ET-1) reported in sickle cell disease correlates with microalbuminuria, an independent risk factor for renal disease progression. In humanized sickle cell mice (HbSS), long-term ETA receptor antagonism significantly attenuated renal tubular iron deposition in proximal tubules (PT). Evidence suggests a pathophysiological links between ET-1, renal iron deposition and early sickle nephropathy, therefore we hypothesize that ET-1 regulates renal iron trafficking in iron overload-associated sickle nephropathy.

Methods

To determine the involvement of ET-1 in renal iron handling mouse primary PT cells (from wild type, HbSS and control (HbAA) mice) were exposed to ET-1 and iron trafficking mediators were assessed by PCR.

Results

Expression of the iron import transporter transferrin receptor 1, TfR-1, and the iron storage protein, H-ferritin, were increased in a concentration-dependent manner by ET-1 in mouse primary PT cells. Also, ET-1 treatment resulted in a decrease in iron exporter ferroportin-1, FPN-1 (65% reduction), which was associated with a doubling in expression of hepcidin, HAMP, a key regulator of FPN-1 and iron removal from the cell. Exposure of PT cells to plasma from HbSS mice, increased cellular iron uptake compared to plasma from control HbAA mice (98±17 vs. 4±1 pg/μl, p<0.05). The ETA antagonist, BQ123, completely prevented ET-1-mediated alterations in all iron mediators, suggesting involvement of ETA receptors in iron trafficking mechanisms. Moreover, plasma ET-1 was positively correlated with renal iron deposition in HbSS mice (R2=0.72, p<0.0001). PT cells isolated from HbSS mice showed significant elevation in expression of TfR-1, DMT-1, H-ferritin, and HAMP along with significantly lower FPN-1 expression compared to control mice. 10-week treatment (from weaning) with an ETA receptor antagonist (ambrisentan 10mg/kg/day) prevented the induction of DMT-1, preserved FPN-1 and reduced HAMP expression in PT cells from HbSS mice.

Conclusion

These results uncover a novel role for ET-1 in PT iron trafficking and provide a rationale for the use of selective ETA receptor blockade as a therapeutic approach in iron overload-associated sickle nephropathy.

Funding

  • NIDDK Support