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Combined hydroxyurea and ETA receptor blockade on renal dysfunction in the humanized sickle mouse
Author(s) -
Taylor Crystal Monique,
Kasztan Malgorzata,
Tao Binli,
Pollock Jennifer S,
Pollock David
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1030.1
Subject(s) - medicine , ambrisentan , renal function , pathophysiology , kidney , endocrinology , acute kidney injury , proteinuria , pharmacology , receptor , endothelin receptor , bosentan
Sickle cell disease (SCD) is associated with an increasing incidence of kidney disease, and the underlying causes have not been elucidated. Recent data has from our lab and others have shown that the vaso‐active peptide endothelin‐1 (ET‐1) plays a critical role in the pathophysiology of sickle cell nephropathy (SCN) and the blockade of its ETA receptor improves renal function and reduces renal injury. As hydroxyurea (HU) is a commonly prescribed drug for the treatment of SCD due to its ability to increase fetal hemoglobin, investigating how these two complex systems interact in the pathophysiology of SCN could provide insight into pathophysiologic mechanisms. Therefore, we hypothesized that combined ambrisentan (ETA selective antagonist) and HU treatment has a synergistic effect on renal injury in SCN when compared to HU treatment alone. Male 12 week old humanized sickle mice (Towne's mice; HbSS) and their genetic controls (HbAA) were treated with either vehicle (drinking water), HU (50mg/kg/day), or HU plus ambrisentan (10mg/kg/day). After 2 weeks of treatment, mice were placed in metabolic cages to assess renal function and then euthanized for blood and tissue collection. Vehicle treated HbSS mice exhibited significant proteinuria (4.38 ± 0.89 mg/day, p=0.0082), elevated plasma ET‐1 concentration (2.68 ± 0.44 pg/ml, p=0.01), and urinary ET‐1 excretion (1.43 ± 0.17pg/day, p=0.0042) as well as decreased urine osmolarity (1205 ± 63.3 mOsmol/kg, p<0.0001) compared to HbAA controls. This renal injury phenotype was significantly attenuated in the HU treated animals (2.09 ± 0.28 mg/day, 0.881± 0.100 pg/ml, 0.336 ± 0.05 pg/day, 1686 ± 83.1mOsmol/kg, respectively; p<0.05 compared to HbSS vehicle treated for all analyses); however, there was no additional improvement in HbSS mice treated with combined ambrisentan and HU. The absence of further attenuation of renal injury with combined treatment suggests that the mechanism of action for both treatments may converge on the same mechanistic pathway.