Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice

• DOI: 10.1681/asn.2016070711
• Publication Date: 2017-03-28T00:22:12Z
• Authors: Malgorzata Kasztan; Brandon M. Fox; Joshua S. Speed; Carmen De Miguel; Eman Y. Gohar; Tim M. Townes; Abdullah Kutlar; Jennifer S. Pollock; David M. Pollock
• Keywords: Ambrisentan; Humanized mouse; Albuminuria

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because the lack efficacious treatments targeting renal manifestations disease. Here, we describe long-term treatment strategy with selective endothelin-A receptor (ETA) antagonist, ambrisentan, designed to interfere development humanized mouse model SCD. Ambrisentan preserved GFR at level nondisease controls prevented proteinuria, albuminuria, nephrinuria. Microscopy studies demonstrated prevention podocyte loss structural alterations, absence vascular congestion, attenuation glomerulosclerosis treated mice. Studies isolated glomeruli showed that reduced inflammation oxidative stress. At tubules, ambrisentan increased excretion urinary tubular injury biomarkers. Additionally, brush border loss, diminished iron deposition, blocked interstitial fibrosis, immune infiltration. Furthermore, albuminuria mice was associated preservation cortical megalin expression. In separate series identical experiments, combined ETA ETB antagonism provided only some protection observed highlighting importance exclusively Our results demonstrate provides robust from diverse pathologies SCD mice, suggest may provide for complications