Dataset Information

Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience.

ABSTRACT: Prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF), which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHI [prolyl hydroxylase inhibitor]) stimulate the production of endogenous erythropoietin and improve iron metabolism resulting in efficacious anemia management in patients with CKD. Three oral HIF-PHIs-daprodustat, roxadustat, and vadadustat-have now advanced to global phase III clinical development culminating in the recent licensing of roxadustat for oral anemia therapy in China. Here, we survey current clinical experience with HIF-PHIs, discuss potential therapeutic advantages, and deliberate over safety concerns regarding long-term administration in patients with renal anemia.

SUBMITTER: Sanghani NS

PROVIDER: S-EPMC7318915 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience.

Sanghani Neil S NS Haase Volker H VH

Advances in chronic kidney disease 20190701 4

Prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF), which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHI [prolyl hydroxylase inhibitor]) stimulate the production of endogenous erythropoietin and improve iron metabolism resulting in efficacious anemia management in patients with CKD. Three oral H ...[more]

PMID: 31477256

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Project description:OBJECTIVE:Mural angiogenesis and macrophage accumulation are two pathologic hallmarks of abdominal aortic aneurysm (AAA) disease. The heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) is an essential regulator of angiogenesis and macrophage function. In this study, we investigated HIF-1 expression and activity in clinical and experimental AAA disease. METHODS:Human aortic samples were obtained from 24 AAA patients and six organ donors during open abdominal surgery. Experimental AAAs were created in 10-week-old male C57BL/6J mice by transient intra-aortic infusion of porcine pancreatic elastase (PPE). Expression of HIF-1? and its target gene messenger RNA (mRNA) levels were assessed in aneurysmal and control aortae. The HIF-1? inhibitors 2-methoxyestradiol and digoxin, the prolyl hydroxylase domain-containing protein (PHD) inhibitors cobalt chloride and JNJ-42041935, and the vehicle alone as control were administered daily to mice at varying time points beginning before or after PPE infusion. Influences on experimental AAA formation and progression were assessed by serial transabdominal ultrasound measurements of aortic diameter and histopathologic analysis at sacrifice. RESULTS:The mRNA levels for HIF-1?, vascular endothelial growth factor A, glucose transporter 1, and matrix metalloproteinase 2 were significantly increased in both human and experimental aneurysm tissue. Tissue immunostaining detected more HIF-1? protein in both human and experimental aneurysmal aortae compared with respective control aortae. Treatment with either HIF-1? inhibitor, beginning before or after PPE infusion, prevented enlargement of experimental aneurysms. Both HIF-1? inhibition regimens attenuated medial elastin degradation, smooth muscle cell depletion, and mural angiogenesis and the accumulation of macrophages, T cells, and B cells. Whereas mRNA levels for PHD1 and PHD2 were elevated in experimental aneurysmal aortae, pharmacologic inhibition of PHDs had limited effect on experimental aneurysm progression. CONCLUSIONS:Expression of HIF-1? and its target genes is increased in human and experimental AAAs. Treatment with HIF-1? inhibitors limits experimental AAA progression, with histologic evidence of attenuated mural leukocyte infiltration and angiogenesis. These findings underscore the potential significance of HIF-1? in aneurysm pathogenesis and as a target for pharmacologic suppression of AAA disease.

Dataset Information

Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience.

Publications

Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience.

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