Combined hydroxyurea and ET<sub>A</sub> receptor blockade reduces renal injury in the humanized sickle cell mouse

Taylor, Chris; Kasztan, Małgorzata; Tao, Binli; Pollock, Jennifer S.; Pollock, David M.

doi:10.1111/apha.13178

Cited by 11 publications

(4 citation statements)

References 62 publications

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“…Sickle cell disease (SCD) is being increasingly recognized as a cause of CKD [46]. Renal ET-1 is increased in patients with SCD; ETA antagonism, either alone or in combination with hydroxyurea, ameliorates renal disease progression in a mouse model of SCD [47,48]. The ET system may also contribute to other aspects of SCD; an EDN1 gene polymorphism is associated with vaso-occlusive crisis risk in patients with SCD [49].…”

Section: Endothelin Receptor Antagonist In Other Etiologies Of Chroni...mentioning

confidence: 99%

Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease

Smeijer

Kohan

Webb

et al. 2021

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewTo summarize new clinical findings of endothelin receptor antagonists (ERA) in various etiologies of kidney disease targeted in clinical trials. Recent findingsEndothelin-1 is a multifunctional peptide with potential relevance to glomerular and tubulointerstitial kidney diseases. The phase 3 SONAR trial demonstrated a significant reduction in clinically relevant kidney outcomes for patients with diabetic kidney disease (DKD) after long-term treatment with the ERA, atrasentan, in addition to blockade of the renin-angiotensin-aldosterone system. Promising preclinical disease models and small clinical trials in non-DKD resulted in the initiation of phase 3 trials investigating the effects of long-term treatment with ERA in patients with immunoglobulin A (IgA) nephropathy and focal segmental glomeruloscelerosis (FSGS). The mechanisms by which ERA protects the kidneys have been extensively studied with evidence for the protection of tubule cells, podocytes, mesangial cells, the endothelial glycocalyx, and a reduction in glomerular perfusion pressure. The occurrence of fluid retention during ERA treatment, particularly in susceptible populations, necessitates strategies to support safe and effective treatment.

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Section: Endothelin Receptor Antagonist In Other Etiologies Of Chroni...mentioning

confidence: 99%

Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease

Smeijer

Kohan

Webb

et al. 2021

Current Opinion in Nephrology &Amp; Hypertension

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“…Endothelin-1 is a potent vasoconstrictor and bronchoconstrictor, whose plasma and urinary values are increased in SCD subjects in steady state and during acute VOCs 18,90,91. In a mouse model for SCD, the ET-1 receptors’ blocker, bosentan, prevented hypoxia induced organ damage and affect neutrophil mediated inflammatory response, suggesting the modulation of the ET-1 system as an additional therapeutic option to interfere with the pathogenesis of SCD related clinical manifestation(s) 18,92,93. It is of interest to note that increased ET-1 and high ET-1 levels have been shown to positively correlate with pain rating in children with SCD 94.…”

Section: Novel Therapeutic Approaches To Treat Sickle Cell Diseasementioning

confidence: 99%

New Therapeutic Options for the Treatment of Sickle Cell Disease

Mattè

Zorzi

Mazzi

et al. 2019

Mediterr J Hematol Infect Dis

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Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality. Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD.New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy. The pathophysiology related novel therapies are: a) Agents which reduce sickling or prevent sickle red cell dehydration; b) Agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) Anti-oxidant agents.This review highlights new therapeutic strategies in SCD and discusses future developments, research implications, and possible innovative clinical trials.

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“…Under pathophysiological conditions the ET system can be deranged and can contribute to kidney disease development and progression. In diabetic nephropathy, sickle cell nephropathy (14)(15)(16)(17), or hypertensive kidney disease (18,19), excess ET-1 has been recognized as a mediator of kidney hemodynamics alterations, glomerular permeability, and kidney injury. These preclinical findings have translated into clinical practice, as recently there have been clinical trials using endothelin receptor antagonists (ERAs).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of the endothelin system in the kidneys of mice, rats, and humans

Patel,

Harris,

Kasztan

et al. 2024

Bioscience Reports

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The intrarenal endothelin (ET) system is an established moderator of kidney physiology and mechanistic contributor to the pathophysiology and progression of chronic kidney disease in humans and rodents. The aim of this study was to characterize ET system by combining single cell RNA sequencing (scRNA-seq) data with immunolocalization in human and rodent kidneys of both sexes. Using publicly available scRNA-seq data we assessed sex and kidney disease status (human), age and sex (rats), and diurnal expression (mice) on the kidney ET system expression. In normal human biopsies of both sexes and in rodent kidney samples, the endothelin converting enzyme-1 (ECE1) and ET-1 were prominent in the glomeruli and endothelium. These data agreed with the scRNA-seq data from these 3 species, with ECE1/Ece1 mRNA enriched in the endothelium. However, the EDN1/Edn1 gene (encodes ET-1) was rarely detected, even though it was immunolocalized within the kidneys, and plasma and urinary ET-1 excretion are easily measured. Within each species, there were some sex-specific differences. For example, in kidney biopsies from living donors, men had a greater glomerular endothelial cell endothelin receptor B (Ednrb) compared to women. In mice, females had greater kidney endothelial cell Ednrb than male mice. As commercially available antibodies did not work in all species, and RNA expression did not always correlate with protein levels, multiple approaches should be considered to maintain required rigor and reproducibility of the pre- and clinical studies evaluating the intrarenal ET system.

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Combined hydroxyurea and ET_A receptor blockade reduces renal injury in the humanized sickle cell mouse

Abstract: These findings indicate that HU and ET receptor blockade produce similar reductions in renal injury in the humanized sickle mouse suggesting that both treatments may converge on the same mechanistic pathway.

Cited by 11 publications

References 62 publications

Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease

Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease

New Therapeutic Options for the Treatment of Sickle Cell Disease

Comprehensive analysis of the endothelin system in the kidneys of mice, rats, and humans

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Combined hydroxyurea and ETA receptor blockade reduces renal injury in the humanized sickle cell mouse

Abstract: These findings indicate that HU and ET receptor blockade produce similar reductions in renal injury in the humanized sickle mouse suggesting that both treatments may converge on the same mechanistic pathway.

Cited by 11 publications

References 62 publications

Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease

Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease

New Therapeutic Options for the Treatment of Sickle Cell Disease

Comprehensive analysis of the endothelin system in the kidneys of mice, rats, and humans

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Product

Resources

About

Combined hydroxyurea and ET_A receptor blockade reduces renal injury in the humanized sickle cell mouse