Abstract: SA-PO1171
Endothelin-1 Promotes Renal Iron Deposition in Murine Models of Iron Overload
Session Information
- NIDDK KUH Summer Undergraduate Research Program Posters
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Anemia and Iron Metabolism
- 201 Anemia and Iron Metabolism: Basic
Author
Group or Team Name
- Rachel Meek. The University of Alabama at Birmingham, Birmingham, AL.
Background
Recent observations show that renal iron deposition correlates with plasma endothelin-1 (ET-1) in sickle cell disease (SCD). Iron accumulation in humanized SCD mice kidneys is ameliorated by a selective endothelin A receptor (ETA) antagonist, ambrisentan. Thus, we hypothesized that endothelial-derived ET-1 regulates iron trafficking in the kidney.
Methods
Vascular endothelial cell ET-1 knockout (VEET KO) male mice aged 12 weeks were injected with phenylhydrazine (40 mg/kg, IP) for two consecutive days to induce hemolysis and consequent iron overload. Heme oxygenase-1 knockout (HO-1 KO) mice, a model of iron overloading, aged 20 weeks were given ambrisentan (10 mg/kg/day, p.o.) for 4 weeks.
Results
VEET KO mice exhibited a higher survival rate relative to littermate control mice (66.7% vs 20% survival, n=9 and 5, respectively). Moreover, VEET KO mice with induced hemolysis have less renal iron deposition when compared with control mice (Prussian blue staining, 41.1 ± 5.1 vs 79.3 ± 0 Mpixel/μm, respectively). At baseline, iron trafficking mediators (TRF-1, DMT-1, FtH, FPN-1) assessed by RT-PCR were not upregulated in VEET KO mice when compared with control mice.
HO-1 KO mice exhibited elevated plasma ET-1 (2.59 ± 0.78 vs 0.45 ± 0.09 pg/mL), cortical ET-1 mRNA expression (2-fold increase), and renal iron content (87.2 ± 27.5 vs 0.24 ± 0.2 Mpixel/μm) when compared with control mice; all were significantly reduced by ambrisentan. No significant changes in expression of iron uptake and storage mediators in KO mice. Ferroportin-1, an iron exporter, was significantly increased by ambrisentan.
Conclusion
These data suggest ET-1 contributes to renal iron overload.