Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice

Huang, Liang; Chou, Hsiu Chu; Chen, Chung-Ming

doi:10.1016/j.pedneo.2021.03.012

Cited by 10 publications

(9 citation statements)

References 38 publications

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“…Due to the lack of a specific antibody against mouse HIF2α protein, this hypothesis could not be tested so far. If postnatal HIF2α activity despite high environmental oxygen levels is actually key for the correct alveolarization of the lung, this might explain why PHD inhibition ameliorates the lung hypoplasia observed in mouse models of hyperoxiainduced lung injury [37,38] or in primate models of bronchopulmonary dysplasia [39,40]. Our data support these previous concepts of a selective use of HIF-stabilizing agents in order to promote proper vascularization of the interstitial pulmonary tissue in very premature infants.…”

Section: Discussionsupporting

confidence: 82%

Adaptation of the Oxygen Sensing System during Lung Development

Kirschner

Kelterborn

Stehr

et al. 2022

Oxidative Medicine and Cellular Longevity

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During gestation, the most drastic change in oxygen supply occurs with the onset of ventilation after birth. As the too early exposure of premature infants to high arterial oxygen pressure leads to characteristic diseases, we studied the adaptation of the oxygen sensing system and its targets, the hypoxia-inducible factor- (HIF-) regulated genes (HRGs) in the developing lung. We draw a detailed picture of the oxygen sensing system by integrating information from qPCR, immunoblotting, in situ hybridization, and single-cell RNA sequencing data in ex vivo and in vivo models. HIF1α protein was completely destabilized with the onset of pulmonary ventilation, but did not coincide with expression changes in bona fide HRGs. We observed a modified composition of the HIF-PHD system from intrauterine to neonatal phases: Phd3 was significantly decreased, while Hif2a showed a strong increase and the Hif3a isoform Ipas exclusively peaked at P0. Colocalization studies point to the Hif1a-Phd1 axis as the main regulator of the HIF-PHD system in mouse lung development, complemented by the Hif3a-Phd3 axis during gestation. Hif3a isoform expression showed a stepwise adaptation during the periods of saccular and alveolar differentiation. With a strong hypoxic stimulus, lung ex vivo organ cultures displayed a functioning HIF system at every developmental stage. Approaches with systemic hypoxia or roxadustat treatment revealed only a limited in vivo response of HRGs. Understanding the interplay of the oxygen sensing system components during the transition from saccular to alveolar phases of lung development might help to counteract prematurity-associated diseases like bronchopulmonary dysplasia.

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Section: Discussionsupporting

confidence: 82%

Adaptation of the Oxygen Sensing System during Lung Development

Kirschner

Kelterborn

Stehr

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…50 RXD alleviates hyperoxia-induced lung injury in newborn mice by enhancing the expression of proangiogenetic factor and stabilising HIF-1α. 51 RXD accelerates wound healing in diabetic rats by promoting angiogenesis through HIF-1α/VEGF signalling. 16 Our results also demonstrate that RXD promoted the expression of HIF-1α dose-dependently.…”

Section: Discussionmentioning

confidence: 99%

Roxadustat promotes hypoxia‐inducible factor‐1α/vascular endothelial growth factor signalling to enhance random skin flap survival in rats

Lan

Wang

Meng

et al. 2023

International Wound Journal

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Random skin flaps have limited clinical application as a broad surgical reconstruction treatment because of distal necrosis. The prolyl hydroxylase domain‐containing protein inhibitor roxadustat (RXD) enhances angiogenesis and reduces oxidative stress and inflammation. This study explored the function of RXD in the survival of random skin flaps. Thirty‐six male Sprague–Dawley rats were randomly divided into low‐dose RXD group (L‐RXD group, 10 mg/kg/2 day), high‐dose RXD group (H‐RXD group, 25 mg/kg/2 day), and control group (1 mL of solvent, 1:9 DMSO:corn oil). The proportion of surviving flaps was determined on day 7 after surgery. Angiogenesis was assessed by lead oxide/gelatin angiography, and microcirculation blood perfusion was evaluated by laser Doppler flow imaging. Specimens in zone II were obtained, and the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured as indicators of oxidative stress. Histopathological status was evaluated with haematoxylin and eosin staining. The levels of hypoxia‐inducible factor‐1α (HIF‐1α), vascular endothelial growth factor (VEGF), and the inflammatory factors interleukin (IL)‐1β, IL‐6, and tumour necrosis factor‐α (TNF‐α) were detected by immunohistochemistry. RXD promoted flap survival and microcirculatory blood perfusion. Angiogenesis was detected distinctly in the experimental group. SOD activity increased and the MDA level decreased in the experimental group. Immunohistochemistry indicated that the expression levels of HIF‐1α and VEGF were increased while the levels of IL‐6, IL‐1β, and TNF‐α were decreased after RXD injection. RXD promoted random flap survival by reinforcing vascular hyperplasia and decreasing inflammation and ischaemia‐reperfusion injury.

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“…A study of renal IRI in mice reported that roxadustat attenuated renal injury by enhancing renal angiogenesis and tissue repair due to its upregulation of HIF (Wu et al, 2021). A study of neonatal Frontiers in Pharmacology frontiersin.org mice found that intraperitoneal roxadustat upregulated the expression of HIF-1α, VEGF, and endothelial NO synthase, promoted alveolar normalization and angiogenesis, and alleviated hyperoxia-induced lung injury (Huang et al, 2021). Another study of roxadustat reported that it significantly upregulated VEGF production in rats and bone marrow mesenchymal stem cells, and also promoted fracture healing (Chen et al, 2021).…”

Section: Effect Of Roxadustat On Angiogenesismentioning

confidence: 99%

Roxadustat: Not just for anemia

Zhu

Jiang²,

Wei³

et al. 2022

Front. Pharmacol.

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Roxadustat is a recently approved hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated favorable safety and efficacy in the treatment of renal anemia. Recent studies found it also has potential for the treatment of other hypoxia-related diseases. Although clinical studies have not yet found significant adverse or off-target effects of roxadustat, clinicians must be vigilant about these possible effects. Hypoxia-inducible factor regulates the expression of many genes and physiological processes in response to a decreased level of oxygen, but its role in the pathogenesis of different diseases is complex and controversial. In addition to increasing the expression of hypoxia-inducible factor, roxadustat also has some effects that may be HIF-independent, indicating some potential off-target effects. This article reviews the pharmacological characteristics of roxadustat, its current status in the treatment of renal anemia, and its possible effects on other pathological mechanisms.

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Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice

Cited by 10 publications

References 38 publications

Adaptation of the Oxygen Sensing System during Lung Development

Adaptation of the Oxygen Sensing System during Lung Development

Roxadustat promotes hypoxia‐inducible factor‐1α/vascular endothelial growth factor signalling to enhance random skin flap survival in rats

Roxadustat: Not just for anemia

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