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

Malignant tumors of the central nervous system (CNS) continue to be a leading cause of cancerrelated mortality in both children and adults. Traditional therapies for malignant brain tumors consist of surgical resection and adjuvant chemoradiation; such approaches are often associated with extreme morbidity. Accordingly, novel, targeted therapeutics for neoplasms of the CNS, such as immunotherapy with oncolytic engineered herpes simplex virus (HSV) therapy, are urgently warranted. Herein, we discuss treatment challenges related to HSV virotherapy delivery, entry, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Sickle cell disease is associated with acute painful episodes and chronic intractable pain. Endothelin-1, a known pain inducer, is elevated in the blood plasma of both sickle cell patients and mouse models of sickle cell disease. We show here that the levels of endothelin-1 and its endothelin type A receptor are increased in the dorsal root ganglia of a mouse model of sickle cell disease. Pharmacologic inhibition or neuron-specific knockdown of endothelin type A receptors in primary sensory neurons of dorsal root ganglia alleviated basal and post-hypoxia evoked pain hypersensitivities in sickle cell mice. Mechanistically, endothelin type A receptors contribute to sickle cell disease-associated pain likely through the activation of NF-κB-induced Nav1.8 channel upregulation in primary sensory neurons of sickle cell mice. Our findings suggest that endothelin type A receptor is a potential target for the management of sickle cell disease-associated pain, although this expectation needs to be further verified in clinical settings.

The renal tubular epithelial cells produce more endothelin-1 (ET-1) than any other cell type in the body. Moving down the nephron, the amount of ET-1 produced appears fairly consistent until reaching the inner medullary collecting duct, which produces at least 10 times more ET-1 than any other segment. ET-1 inhibits Na+ transport in all parts of the nephron through activation of the ETB receptor, and to a minor extent, the ETA receptor. These effects are most prominent in the collecting duct where ETB receptor activation inhibits activity of the epithelial Na+ channel. Effects in other parts of the nephron include inhibition of Na+/H+ exchange in the proximal tubule and the Na+, K+, 2Cl− co-transporter in the thick ascending limb. In general, the renal epithelial ET-1 system is an integral part of the body’s response to a high salt intake in order to maintain homeostasis and normal blood pressure. Loss of ETB receptor function results in salt sensitive hypertension. The goal of this article is to review the role of renal ET-1 and how it affects Na+ and water transport throughout the nephron.