Hypoxia-Inducible Factor Stabilizers: a New Avenue for Reducing BP While Helping Hemoglobin?

Yousaf, Farhanah; Spinowitz, Bruce

doi:10.1007/s11906-016-0629-6

Cited by 22 publications

(23 citation statements)

References 181 publications

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“…Potential upregulation of the vascular endothelial growth factor (VEGF) gene as a result of HIF stabilization could adversely impact tumor growth and accelerate proliferative retinopathy in diabetics. Phase II studies in vadadustat and daprodustat have not demonstrated any significant change in VEGF, and in a VEGF-sensitive model of spontaneous breast cancer, roxadustat was not associated with tumor initiation, progression, or metastases [68,72].…”

Section: Discussionmentioning

confidence: 97%

“…With the former, both daprodustat and roxadustat, but not vadadustat, have been shown to reduce lipids, with no published data on molidustat. There is very limited evidence to support any role in reducing blood pressure, although this will be explored in phase III trials [68]. The pleiotropic effects of the HIF pathway, however, do raise some potential concerns regarding safety, which will be addressed in the phase III trials.…”

Section: Discussionmentioning

confidence: 99%

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HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

Kular

Macdougall

2018

Pediatr Nephrol

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Anemia is a common complication of chronic kidney disease (CKD) in adult and pediatric patients. It has traditionally been treated with erythropoietin therapy and iron supplementation, with great success. With the discovery of the major transcription factor hypoxia inducible factor (HIF) for the erythropoietin gene in 1992, molecules were created that inhibit the HIF prolylhydroxylase enzyme. This new class of drug-called HIF stabilizers, or HIF prolyl-hydroxylase inhibitors-prevents the proteasomal degradation of HIF-α, thereby inducing upregulation of the erythropoietin gene. This new strategy for treating CKD anemia is already in phase III clinical trials in adults, and the potential advantages of this therapy are that it is orally active (thereby avoiding injections), and patients are exposed to lower circulating levels of erythropoietin. The long-term safety of this strategy, however, requires elucidation in these trials, particularly since there are many other hypoxia-sensitive genes, notably, angiogenic factors such as vascular endothelial growth factors (VEGF), as well as glycolytic enzymes. As with all new therapies, it is only once a positive benefit: risk profile has been ascertained in adults that the treatment will translate across into pediatrics. Specific issues in the pediatric CKD population are discussed in this review.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

Kular

Macdougall

2018

Pediatr Nephrol

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“…These agents have been applied to the treatment of renal anaemia in which there is a deficiency of erythropoietin [22,23]. The administration of these compounds is associated with an improved iron profile and an increase of endogenous erythropoietin production to near the physiological range.…”

Section: Consequences Of Hypoxiamentioning

confidence: 99%

“…The clinical trials currently underway aim to address whether PHD enzyme inhibitors will improve clinical end-points, including cardiovascular events [24]. PHD inhibitors have been reported to reduce blood pressure [22] and plasma cholesterol concentrations [19]. Hence, there is a good reason to believe that some PHD inhibitors will reduce cardiovascular endpoints in patients with renal disease.…”

Section: Consequences Of Hypoxiamentioning

confidence: 99%

Hypoxia, Angiogenesis and Atherogenesis

Heikal¹,

Ferns²

2017

Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

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The balance between vascular oxygen supply and metabolic demand for oxygen within the vasculature is tightly regulated. An imbalance leads to hypoxia and a consequential cascade of cellular signals that attempt to offset the effects of hypoxia. Hypoxia is invariably associated with atherosclerosis, wound repair, inflammation and vascular disease.There is now substantial evidence that hypoxia plays an essential role in angiogenesis as well as plaque angiogenesis. It controls the metabolism, and responses of many of the cell types found within the developing plaque and whether the plaque will evolve into a stable or unstable phenotype. Hypoxia is characterized in molecular terms by the stabilization of hypoxia-inducible factor (HIF)-1α, a subunit of the heterodimeric nuclear transcriptional factor HIF-1 and a master regulator of oxygen homeostasis. The expression of HIF-1 is localized to perivascular tissues, inflammatory macrophages and smooth muscle cells where it regulates several genes that are important to vascular function including vascular endothelial growth factor, nitric oxide synthase, endothelin-1 and erythropoietin. This chapter summarizes the effects of hypoxia on the functions of cells involved in angiogenesis as well as atherogenesis (plaque angiogenesis) and the evidence for its potential importance from experimental models and clinical studies.

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“…Accruing evidence has suggested that the balance between HIF-1α and HIF-2α is of crucial importance for the maintenance of systemic arterial pressure [41] . Transcription of HIF-1α leads to an increased expression of NO synthase 2 and consequently increased NO production whereas transcription of HIF-2α indirectly reduces NO production [42,43] .…”

Section: Concerns With Hif Stabilizersmentioning

confidence: 99%

Novel Masters of Erythropoiesis: Hypoxia Inducible Factors and Recent Advances in Anemia of Renal Disease

Solak¹,

Çetiner²,

Siriopol³

et al. 2016

Blood Purif

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Anemia seen in patients with chronic kidney disease is a particular form of ‘anemia of chronic disease'. Although multifactorial in origin, erythropoiesis-stimulating agents (ESAs) and adjuvant iron therapy represent the primary treatment for anemia in chronic kidney disease. Subsequent clinical observations revealed that these ESA hyporesponsive patients often had increased systemic inflammation as a consequence of their comorbidities. Use of high ESA doses to overcome this ESA hyporesponsiveness posed some concerns regarding associated adverse events of therapy and increased mortality in this special patient population. Recognizing the pivotal roles of hypoxia inducible factors (HIFs) in orchestrating elements of erythropoiesis opened new avenues in the management of renal anemia. Several phase 1 and 2 studies confirmed the results of early experimental studies supporting the beneficial role of augmenting HIFs for erythropoiesis. In this review, we describe the physiologic functions of HIF in erythropoiesis with special emphasis on interactions with iron and hepcidin metabolism and inflammation.

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Hypoxia-Inducible Factor Stabilizers: a New Avenue for Reducing BP While Helping Hemoglobin?

Cited by 22 publications

References 181 publications

HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

Hypoxia, Angiogenesis and Atherogenesis

Novel Masters of Erythropoiesis: Hypoxia Inducible Factors and Recent Advances in Anemia of Renal Disease

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