Kidney Week

Abstract: SA-PO325

Renal Iron Trafficking – Potential Role for Endothelin System

Session Information

• Mechanisms Associated with Kidney Fibrosis - II
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Chronic Kidney Disease (Non-Dialysis)

• 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

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

Malgorzata Kasztan,

• 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 endothelin-1 (ET-1) levels reported in sickle cell disease correlate with microalbuminuria, linking ET-1, renal iron deposition and early sickle nephropathy. In humanized sickle cell mice (HbSS), long-term ET_A receptor antagonism provides robust protection from diverse renal pathologies, including significant attenuation of renal tubular iron deposition in proximal tubules (PT). We hypothesize that ET-1 regulates renal iron trafficking in iron overload-associated sickle nephropathy.

Methods

We first determined the time and concentration-dependent effect of ET-1 on the expression of iron trafficking mediators in mouse primary PT epithelial cells.

Results

Expression of the iron import transporter transferrin receptor 1, TfR-1, and the iron storage protein, H-ferritin, were increased in concentration-dependent manner by ET-1. The ET-1-induced decrease in iron exporter ferroportin-1, FPN-1 (65% reduction), 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 cell to plasma from HbSS mice, increased cellular iron uptake compared to plasma from control HbAA mice (0.098±0.017 vs. 0.004±0.001 ng/μl). The ET_A antagonist, BQ123, completely prevented ET-1-induced alterations in all iron mediators, suggesting involvement of ET_A receptor in iron trafficking mechanisms. Neither selective ET_B nor combined (ET_A+ET_B) antagonism affected ET-1-induced changes in iron trafficking mediators. Cortical tissues of HbSS mice showed increased expression of TfR-1, H-ferritin and decreased expression of FPN-1 compared to HbAA mice.

Conclusion

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

Funding

• NIDDK Support