title: Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice.
abstract: Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ETA) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ETAand ETBreceptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ETAreceptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ETAreceptor antagonism may provide a strategy for the prevention of renal complications of SCD.
authors.affiliation: Cardio-Renal Physiology and Medicine, Department of Medicine, and.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kasztan
authors.affiliation: Cardio-Renal Physiology and Medicine, Department of Medicine, and.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Fox
authors.affiliation: Cardio-Renal Physiology and Medicine, Department of Medicine, and.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Speed
authors.affiliation: Cardio-Renal Physiology and Medicine, Department of Medicine, and.
authors.forename: Carmen
authors.initials: C
authors.lastname: De Miguel
authors.affiliation: Cardio-Renal Physiology and Medicine, Department of Medicine, and.
authors.forename: Eman Y
authors.initials: EY
authors.lastname: Gohar
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Townes
authors.affiliation: Division of Hematology and Oncology, and.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.affiliation: Cardio-Renal Physiology and Medicine, Department of Medicine, and.|Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pollock
authors.affiliation: Cardio-Renal Physiology and Medicine, Department of Medicine, and dpollock@uab.edu.|Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: David M
authors.initials: DM
authors.lastname: Pollock
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications*; D000818:Animals; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D010666:Phenylpropionates / Q000627:therapeutic use*; D011724:Pyridazines / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D065130:Endothelin A Receptor Antagonists; D010666:Phenylpropionates; D011724:Pyridazines; C467894:ambrisentan
keywords: endothelin; glomerular filtration barrier; proteinuria; renal injury; sickle nephropathy