Kidney Week

Abstract: FR-OR102

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

Session Information

• Signaling in CKD Progression
  October 26, 2018 | Location: 23A, San Diego Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Anemia and Iron Metabolism

• 201 Anemia and Iron Metabolism: Basic

Authors

• Kasztan, Malgorzata, University of Alabama at Birmingham, Birmingham, Alabama, United States

Malgorzata Kasztan, PhD

• Hyndman, Kelly A., University of Alabama at Birmingham, Birmingham, Alabama, United States

Kelly A. Hyndman,

• Pollock, David M., University of Alabama at Birmingham, Birmingham, Alabama, United States

David M. Pollock,

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 ET_A 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 ET_A antagonist, BQ123, completely prevented ET-1-mediated alterations in all iron mediators, suggesting involvement of ET_A 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 ET_A 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 ET_A receptor blockade as a therapeutic approach in iron overload-associated sickle nephropathy.

Funding

• NIDDK Support