TY - JOUR
T1 - Long-term endothelin-a receptor antagonism provides robust renal protection in humanized sickle cell disease mice
AU - Kasztan, Malgorzata
AU - Fox, Brandon M.
AU - Speed, Joshua S.
AU - De Miguel, Carmen
AU - Gohar, Eman Y.
AU - Townes, Tim M.
AU - Kutlar, Abdullah
AU - Pollock, Jennifer S.
AU - Pollock, David M.
N1 - Publisher Copyright:
Copyright © 2017 by the American Society of Nephrology.
PY - 2017/8
Y1 - 2017/8
N2 - 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 SCDmice, and suggest that longterm ETA receptor antagonism may provide a strategy for the prevention of renal complications of SCD.
AB - 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 SCDmice, and suggest that longterm ETA receptor antagonism may provide a strategy for the prevention of renal complications of SCD.
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U2 - 10.1681/ASN.2016070711
DO - 10.1681/ASN.2016070711
M3 - Article
C2 - 28348063
AN - SCOPUS:85026539491
SN - 1046-6673
VL - 28
SP - 2443
EP - 2458
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 8
ER -