Long-term endothelin-a receptor antagonism provides robust renal protection in humanized sickle cell disease mice

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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)2443-2458
Number of pages16
JournalJournal of the American Society of Nephrology
Volume28
Issue number8
DOIs
StatePublished - Aug 2017

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Endothelin Receptors
Sickle Cell Anemia
Kidney
Endothelin A Receptors
Albuminuria
Therapeutics
Low Density Lipoprotein Receptor-Related Protein-2
Podocytes
Microvilli
Proteinuria
Blood Vessels
Microscopy
Oxidative Stress
Fibrosis
Iron
Biomarkers
ambrisentan
Pathology
Inflammation
Morbidity

ASJC Scopus subject areas

  • Nephrology

Cite this

Kasztan, M., Fox, B. M., Speed, J. S., De Miguel, C., Gohar, E. Y., Townes, T. M., ... Pollock, D. M. (2017). Long-term endothelin-a receptor antagonism provides robust renal protection in humanized sickle cell disease mice. Journal of the American Society of Nephrology, 28(8), 2443-2458. https://doi.org/10.1681/ASN.2016070711

Long-term endothelin-a receptor antagonism provides robust renal protection in humanized sickle cell disease mice. / Kasztan, Malgorzata; Fox, Brandon M.; Speed, Joshua S.; De Miguel, Carmen; Gohar, Eman Y.; Townes, Tim M.; Kutlar, Abdullah; Pollock, Jennifer S.; Pollock, David M.

In: Journal of the American Society of Nephrology, Vol. 28, No. 8, 08.2017, p. 2443-2458.

Research output: Contribution to journalArticle

Kasztan, M, Fox, BM, Speed, JS, De Miguel, C, Gohar, EY, Townes, TM, Kutlar, A, Pollock, JS & Pollock, DM 2017, 'Long-term endothelin-a receptor antagonism provides robust renal protection in humanized sickle cell disease mice', Journal of the American Society of Nephrology, vol. 28, no. 8, pp. 2443-2458. https://doi.org/10.1681/ASN.2016070711
Kasztan, Malgorzata ; Fox, Brandon M. ; Speed, Joshua S. ; De Miguel, Carmen ; Gohar, Eman Y. ; Townes, Tim M. ; Kutlar, Abdullah ; Pollock, Jennifer S. ; Pollock, David M. / Long-term endothelin-a receptor antagonism provides robust renal protection in humanized sickle cell disease mice. In: Journal of the American Society of Nephrology. 2017 ; Vol. 28, No. 8. pp. 2443-2458.
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