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 ETA and ETB receptor antagonism provided only some of the protection observed with
ambrisentan, highlighting the importance of exclusively targeting the ETA receptor in SCD. Our results demonstrate that
ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ETA receptor antagonism may provide a strategy for the prevention of renal complications of SCD.