A Pharmacodynamic Evaluation of the Protective Effects of Roxadustat Against Hypoxic Injury at High Altitude

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Methods: BALB/C mice were randomly divided into control, roxadustat-7.8 mg/kg, roxadustat-15.6 mg/kg and roxadustat-31.2 mg/kg groups. The anti-hypoxic effectiveness of roxadustat in an optimal dose was evaluated by atmospheric pressure closed hypoxic experiment. Wistar rats were randomly divided into normal pressure, hypoxia model, acetazolamide and roxadustat groups to evaluate the protective effects against hypoxic damage. Animal blood was collected for arterial blood-gas analysis, cytokines detection, oxidative stress indicators, and their organs were harvested for pathological examination. Results: Compared with the control group, the survival time of mice were significantly prolonged in all groups. The time prolongation rate of the medium dose was 19.05%, which was the best dose. Compared with the hypoxia model group, the blood SatO 2 and PaO 2 in the roxadustat group were significantly increased; Erythrocyte content, hemoglobin content and hematocrit were significantly increased; Plasma levels of IL-6, TNF-α and IFN-γ were significantly decreased; MDA content in the myocardial, brain, lung and liver tissue were significantly decreased, SOD activity and GSH content in the tissue were significantly increased. The results of HE staining indicated that roxadustat could significantly improve the damage of heart, brain, lung, liver and kidney tissue after hypoxia in rats. Conlusions: Roxadustat can significantly prevent hypoxia-induced tissue damage, oxidative stress and inflammatory response indicating that roxadustat can obviously improve the adaptation to high-altitude exposure. Roxadustat High Altitude Hypoxia Pharmacodynamics Erythrocyte. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Hypoxia rapidly increases the levels of free radicals in cells and whole-body hypoxia overwhelms the reserves of scavengers, leading to the accumulation of reactive oxygen species (ROS), the release of inflammatory factors and injury of red blood cells (RBC), vascular endothelial cells and other tissues, such as lung, brain and heart, and ultimately leading to life-threatening high-altitude cerebral edoema (HACE) or high-altitude pulmonary edoema (HAPE) (Leaf and Goldfarb 2007 ) . Roxadustat, a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) for the treatment of renal anemia, completed the Phase III clinical trial in China on December 18, 2018, and was approved (Dhillon 2019 ). Proline hydroxylase (PHD) is a rate-limiting enzyme for the degradation of the hypoxic inducible factor (HIF), a regulator of erythropoietin (EPO). EPO promotes erythropoiesis (Haase 2017 ). By inhibiting the rate of PHD to degrade HIF, roxadustat stabilizes the expression of HIF protein to promote the expression of EPO (Long et al. 2020 ; Deguchi et al. 2020 . ). Red blood cells are rich in hemoglobin, which plays a crucial role in the oxygen combination, utilization, transportation, and release (Wang et al. 2011 ). Under hypoxia conditions, roxadustat can improve hypoxemia and alleviate hypoxia by promoting EPO production and increasing red blood cell and hemoglobin content. In the present study, we performed a randomized controlled experimental study based on the experimental animals to evaluate, the anti-hypoxia effect of roxadustat, the pharmacodynamics of roxadustat were preliminarily explored through atmospheric pressure closed hypoxic and acute altitude field hypoxia experiments. Material And Methods Animals A total of 32 male BALB/c mice, weighting 18–22 g each, were provided by 940th Hospital (SYXK (Military) 2020-0032) for the study. Subsequently, 32 mice were randomly divided into 4 groups (n = 8): Control group, roxadustat low-dose group (7.8 mg/kg), medium-dose group (15.6 mg/kg), high-dose group (31.2 mg/kg). A total of 24 healthy Wistar male rats (weight, 200 g ± 2 g), were purchased from Liaoning Changsheng Biotechnology Co. LTD. (SCXK (Liaoning) 2020-0001). The rats were randomly divided into 4 groups (n = 6): Normoxic blank group, hypoxia model group, acetazolamide group (22.5 mg/kg), roxadustat group (10.8 mg/kg). Drug and reagent Roxadustat Capsules (Specification: 20 mg×3 tablets, AstraZeneca Pharmaceutical Co. LTD.); Normal Saline (500 ml: 4.5 g, Shijiazhuang Siyao Pharmaceutical Co. LTD. Batch No. 2007122002); Heparin (Shanghai First Biochemical Pharmaceutical Co. LTD.); Acetazolamide (Purity༞98.0%, Shanghai Yuanye Biotechnology Co. LTD. CAS#59-66-5); Rat TNF-α Elisa kit, Rat IL-6 Elisa kit, MDA kit (Nanjing Jicheng Institute of Bioengineering); Rat EPO Elisa kit (Shanghai Jianglai Industrial Limited by Share LTD.); SOD kit (Nanjing Jiancheng Institute of Biological Engineering); GSH Kit (Nanjing Jiancheng Institute of Biological Engineering); 4% Paraformaldehyde (500 ml, Wuhan Xaver Biotechnology Co. LTD.). Anoxic endurance test under atmospheric pressure 32 BALB/c mice were administrated intragastric for one week, and the equivalent dose of roxadustat was 15.6 mg/kg by body surface area conversion method (Conversion coefficient of mice = (Body size coefficient mouse ×W 2/3 mouse )/(Body size coefficient man ×W 2/3 human ), according to the clinical dose of human. Roxadustat low dose, medium dose and high dose groups were given 0.5 times, 1 time and 2 times of the equivalent dose, namely 7.8 mg/kg, 15.6 mg/kg and 31.2 mg/kg, dissolved in normal saline and assisted with 0.5% carboxymethylcellulose sodium (CMC-Na) and 0.1% tween-80. The control group was given the same amount of solvent once every two days. The experiment was started 1 h after the fourth administration. 40 mice were put into 250 ml jar (put filter paper and sodium lime into the bottle in advance, smear vaseline evenly on the bottle mouth and stopper), per mouse into the bottle and screw down the lid as began to anoxia time, stop breathing in mice, legs no longer tic as a time of death, statistics the survival time of mice and prolong the rate. Field anoxia experiment at high altitude Rats from Lanzhou to gavage in advance to medicine 3 times, roxadustat group and hypoxia model group 1 time two day, acetazolamide group 2 times one day, the fourth day morning by constant temperature after dosing van rats to Xining airport, and then accelerated to Yushu Tibetan autonomous prefecture in Qinghai province high altitude field laboratory (33.1 °N, 96.7 °E, at an altitude of 4,010 m. The temperature was 10 ℃, the humidity was 80%), and the water was freely supplemented with jelly on the way. After arriving in Yushu, the rats underwent acute hypoxia for 3 days. On the fourth day, blood was collected from the ocular venous plexus, anaesthesia with chloral hydrate, and blood was collected from the abdominal aorta. The heart, liver, brain, lung, and kidney tissues were collected for index determination. Determination of blood routine index One hour after administration, 0.5 ml of orbital venous plexus blood was collected from the centrifuge tube rinsed with heparin, and immediately put into an automatic hematology analyzer to measure relevant indexes of blood routine. Measure inflammatory factor index and erythropoietin 1 h after administration, 0.5 ml of orbital venous blood was collected in a heparin-rinsed centrifuge tube, centrifuged at room temperature at 3,500 r/min for 10 min, and the supernatant was taken and stored in a liquid nitrogen tank, which was transported to Lanzhou in strict accordance with IL-6, IFN-γ, TNF-α and EPO ELISA kit for operation. Measure blood gas index After anesthesia, the abdominal cavity of rats was opened and 0.5 ml of abdominal aortic blood was collected, which was immediately determined by a blood gas analyzer. Changes in oxidative stress indicators After collecting the the abdominal aortic blood from rats, the myocardium, liver, brain, lung, and kidney tissues were extracted completely on ice. The blood was washed in pre-cooled normal saline, and the water was drained by filter paper before being stored in liquid nitrogen tanks. During the determination, the tissues were weighed and added with pre-cooled normal saline (M:V = 1:9) in proportion, fully ground in a homogenizer, centrifuged at 4 ℃ at a speed of 4,000 r/min for 10 min, and the supernatant was taken to obtain 10% tissue homogenate. The homogenate was determined in strict accordance with the instructions of the SOD, MDA and GSH kit. HE dyed After collecting the abdominal aortic blood from rats, the myocardium, liver, brain, lung and kidney tissues of 2 rats in each experimental group were extracted completely on ice. The blood stains were washed in pre-cooled normal saline and immediately fixed in 4% paraformaldehyde. In Lanzhou, the tissues were dehydrated, embedded, sliced, and stained with HE. Statistical analysis SPSS 21.0 software was used for statistical analysis, one-way analysis of variance, and an independent sample T test were used for analysis. The statistical results were expressed by mean ± standard deviation, P༜0.05 is a statistical difference. Results Effect of roxadustat on survival time of mice under atmospheric pressure Compared with the control group, the survival time of low, medium, and high dose roxadustat groups were significantly prolonged, with an increased rate of 13.73%, 19.05% and 14.15%, respectively. The results indicate that roxadustat can increase the survival time of mice in atmospheric hypoxia, and the effect of medium-dose is the best (Table.1.). Table.1 Effects of different doses of roxadustat on the survival time of mice. Error bars indicate SD ( n = 8/per group x̄ ±s). Compared with control group, * p< 0.05; ** p< 0.01. Group Dose (mg/kg) Survival time (min) Increase rate control group 28.77 ± 1.91 low dose roxadustat group 7.8 32.72 ± 5.24* 13.73% mediumdose roxadustat group 15.6 34.25 ± 3.64** 19.05% high dose roxadustat group 31.2 32.84 ± 3.40* 14.15% Effects of roxadustat on blood gas in field hypoxia rats at high altitude Compared with normal oxygen group, blood SaO 2 and PaO 2 in the hypoxic group were significantly decreased by 5.81% and 34.49%, respectively (both P<0.01), Hct, pH and Hb contents were significantly increased by 18.00%, 0.68% and 16.31% (all P<0.01) (Table.2.). Compared with the hypoxic group, SaO 2 and PaO 2 in the roxadustat group were significantly increased by 3.21% and 11.56%, respectively (both P<0.01), erythrocyte Hct, pH and Hb contents were significantly decreased by 12.46%, 0.27% and 11.85%, respectively (all P<0.01) (Table.2.). The results indicate that roxadustat can significantly improve the blood gas index of acute altitude hypoxic rats. Table.2 Comparison of blood gas indexes in each group. Error bars indicate SD ( n = 6/per group x̄ ±s).Compared with normal oxygen group, # p <0.05; ## p <0.01; Compared with anoxic blank group, * p <0.05; ** p <0.01. Group SaO2 (%) PaO2 Hct (%) pH (mmHg) Hb (g/L) normal oxygen group 96.7 ± 0.58 90.22 ± 3.47 35.17 ± 1.33 7.39 ± 0.02 118.50 ± 2.74 hypoxic group 91.08 ± 0.46## 59.10 ± 1.64## 41.50 ± 0.55## 7.44 ± 0.01## 137.83 ± 2.14## acetazolamide group 91.47 ± 1.00 64.00 ± 2.08** 36.50 ± 0.84** 7.38 ± 0.01** 123.33 ± 2.50** roxadustat group 94.00 ± 0.72** 65.93 ± 2.84** 36.33 ± 0.52** 7.42 ± 0.03** 121.50 ± 0.84** Effects of roxadustat on blood routine in field hypoxia rats at high altitude Compared with normal oxygen group, RBC and Hb in the hypoxic group were significantly decreased by 10.70% and 37.46%, respectively (both P<0.01), MCV was significantly increased by 15.14% (P<0.01) (Table.3.). Compared with the hypoxic group, RBC, Hb, and HCT in the roxadustat group were significantly increased by 8.00%, 7.62% and 5.09%, respectively (all P<0.01) (Table.3.). The results indicate that roxadustat can significantly improve the blood routine indexes of acute altitude hypoxic rats. Table.3 Comparison of blood routine indexes in each group. Error bars indicate SD ( n = 6/per group x̄ ±s). Compared with normal oxygen blank group, # p <0.05; ## p < 0.01; Compared with anoxic blank group, * p <0.05; ** p <0.01. Group RBC (10^6/uL) Hb (mmol/L) HCT (%) MCV (fl) normal oxygen group 8.97 ± 0.24 16.15 ± 0.68 47.75 ± 2.01 51.38 ± 1.19 hypoxic group 8.01 ± 0.14## 10.10 ± 0.24## 47.70 ± 0.81 59.16 ± 0.99## acetazolamide group 8.17 ± 0.26 10.25 ± 0.21 49.17 ± 0.85 60.28 ± 1.52 roxadustat group 8.65 ± 0.19** 10.87 ± 0.15** 50.13 ± 0.78** 60.60 ± 1.51 Effects of roxadustat on plasma inflammatory factors and EPO in field hypoxia rats at high altitude After 3 days of hypoxia, the results of plasma inflammatory factors showed that the levels of IFN-γ, IL-6 and TNF-α in the hypoxia model group were significantly higher than those in the normoxic blank group. Compared with the hypoxia group, the content of IFN-γ, IL-6 and TNF-α in the roxadustat group significantly decreased by 26.66%, 51.4༅, 42.06༅, and the contents of EPO were significantly increased by 65.44༅ (Fig. 1 .). Effects of roxadustat on oxidative stress in field hypoxia rats at high altitude After 3 days of hypoxia, the results of oxidative stress showed that compared with the normal oxygen group, the SOD activity in renal, lung, and liver tissue in the hypoxia group was significantly decreased (Fig. 2 .D, J and M), and the MDA content in myocardial and lung was significantly increased (Fig. 2 .B and K). The activity of GSH in lung, liver and renal tissue was significantly decreased (Fig. 2 .L, O and F). Compared with the hypoxic group, the SOD activity of brain, lung, liver, and renal tissue in the roxadustat group was significantly increased by 9.64%, 21.61%, 18.68% and 34.98%, respectively (Fig. 2 .G, J, M, and D). MDA content in the myocardial, brain, lung, and liver tissue was significantly decreased by 38.18%, 39.84%, 22.86% and 37.70%, respectively (Fig. 2 .B, H, K, and N). The contents of GSH in myocardial, brain, and renal tissue were significantly increased by 55.84%, 47.03% and 48.80%, respectively (Fig. 2 .C, I and F). The results suggest that roxadustat can ameliorate oxidative stress injury induced by acute altitude hypoxia in rats. Effect of roxadustat on the pathology of field hypoxia rats at high altitude The myocardial fibers in the normal oxygen group were neatly arranged and the nuclei were intact. Compared with the normal oxygen group, myocardial fibers in the hypoxic group were disordered and discontinuous, with wavy fiber fracture and inflammatory cell infiltration (FIG.3.). Compared with the hypoxic group, myocardial fibers in the roxadustat group were arranged neatly, inflammation was reduced, and cytoplasm staining was uniform (FIG.3.). The pyramidal cells in the hippocampus of normal oxygen group were orderly and densely arranged, and the cell structure was normal. Compared with normal oxygen group, pyramidal cells in the hippocampal area of the hypoxic group were disordered and loose, and the cell structure was normal (FIG.4.). Compared with the hypoxic group, the cells in the hippocampal area of the brain tissue of rats in the roxadustat group were arranged neatly and densely, and the cell structure was normal without apparent damage (FIG.4.). In the normal oxygen group, the alveoli of lung tissue showed thin-walled vacuoles with clear nuclei. Compared with the normal oxygen group, the alveolar wall of the hypoxic group was thickened, with incomplete structure, inflammatory cell infiltration and fibrous hyperplasia (FIG.5.). Compared with the hypoxic group, the alveolar wall of the roxadustat group became thinner, the structure tended to be normal, and the inflammatory cells decreased (FIG.5.). Liver tissue cells in the normal oxygen group were arranged in a cord-like structure around the central venous cavity. Compared with the normal oxygen group, the nucleus of liver tissue in the hypoxic group was vacuolated, punctured necrosis was observed, and the hepatic cord structure was not apparent (FIG.6.). Compared with the hypoxic group, liver tissue cells in the roxadustat group did not show vacuolation and spot necrosis (FIG.6.). The cell structure of rat kidney tissue in the normal oxygen group was normal. Compared with the normal oxygen group, the renal tubule epithelial cells in the hypoxic group were edema, the lumen was narrow and tortuous, interstitial capillaries were dilated, and red blood cell exudation was observed in the glomeruli (FIG.7.). Compared with the hypoxic group, the renal tubule epithelial cell edema and glomerular erythrocyte exudation of rats in the roxadustat group were reduced (FIG.7.). Discussion This paper verifies roxadustat has the ability of hypoxia tolerance through atmospheric pressure closed hypoxia experiment. The results showed that roxadustat of the high, medium, and low dose could significantly extend the survival time of hypoxia mice, improve the survival ability of mice in hypoxia, and the survival rate of the medium-dose is the highest, consistent with the human equivalent dose, preliminary showed that roxadustat has anti-hypoxia effect.To verify whether roxadustat has the pharmacodynamic effect of protecting rats against hypoxic injury in the field environment at high altitude, this experiment by determination of high altitude on the spot the arterial blood gas in experimental mice, routine blood, plasma inflammatory cytokines, and myocardial, brain, lung, liver, and kidney tissue of oxidative stress index and pathological damage of roxadust at high altitude hypoxia resistance effect is discussed. It is verified that roxadustat has the pharmacodynamics effect of anti-hypoxic injury in the field environment of high altitude. Previous studies have shown that roxadustat is mainly used in anaemic diseases. Mengqiu Miao et al's study showed that roxadustat can be potentially used in other non-anaemic diseases (Miao, Wu et al. 2022 ). For example, treatment of acute and chronic kidney diseases, prevention of retinopathy of prematurity, promotion of bone and tendon regeneration, treatment of cardiovascular diseases, treatment of respiratory diseases, neuroprotective effect, application in tissue transplantation, anti-tumor and suppression of SARS-CoV-2. In addition, Karin M. Kirschner et al reported that the HIF-PHD like roxadustat can combat hypoxic partial pressure in the treatment of preterm infant diseases (Kirschner, Kelterborn et al. 2022 ), such as bronchial dysplasia. Yukiko Yasuoka et al. found that roxadustat produced EPO in a number of tissues stimulated by hypoxia by exposing rats to 7% oxygen, specifically regulating EPO production in the kidney (Yasuoka, Izumi et al. 2022 ). It is essential to better understand the mechanisms how roxadustat is expected to be a viable drug against high altitude hypoxia, hypoxia stimulates a variety of adaptive responses, many mediated via the HIF family of transcriptional complexes, directly up-regulating transcription of genes involved in erythropoiesis, angiogenesis, vasomotor tone, metabolic pathways and processes related to cell multiplication and survival, and indirectly reducing the transcription of genes with other effects. Hypoxia-inducible factor 1 (HIF-1) is composed of two subunits, HIF-1α and HIF-1β. Hif-1α is a major regulator of oxygen homeostasis, and its oxygen-regulated α chain binds to the constitutive aryl hydrocarbon receptor nuclear translocator. Hif-1α chain degradation is due to oxygen-sensitive hydroxylation of either of the two key prolyl residues in the middle of the HIF-1α chain, known as the oxygen-dependent degradation domain (ODD). This is mediated by one of three families of iron and oxogglutarate dependent enzymes known as PHD1-3, PHD is at the heart of the oxygen-sensing pathway leading to HIF-1α activation. In the presence of adequate amounts of oxygen, iron and 2-oxoglutarate prolyl hydroxyl-ation occurs. The hydroxyprolyl residues produced allow binding of the von Hippel–Lindau E3 ubiquitin ligase complex which causes polyubiquitylation of the HIF-1α chain at a number of lysyl residues which in turn leads to its complete (Kaelin and Ratcliffe 2008 ). Hypoxia inhibits the stability of PHD and HIF-1α. Roxadustat, as a HIF-PHI, can stabilize HIF and inhibit its degradation, reverse the transcription reduction of related genes caused by hypoxia, restore the corresponding physiological response under normoxia, and reduce the damage caused by hypoxia, which proves that Roxadustat does have relevant pharmacological effects. Upon hypoxia, the transcription factor NF-κB is activated by the IKK complex, and IKKβ contains a conserved prolyl hydroxylation site that is homologous to the ODD site of HIF-1α. Hypoxia increases the stability of IKKβ through PHD1 inhibition of IKKβ hydroxylation, and PHD1 directs the separation of NF-κB from its repressor protein, thereby promoting the expression of NF-κB-induced proinflammatory genes. Roxadustat is a HIF-PHI that increases cellular IKKβ activity and NF-κB activity by inhibiting PHD activity. Nf-κβ directly regulates HIF-1α, an event that amplifies the ability of cells to respond to cytokines (Cummins et al. 2006 ). Hypoxia can induce adaptive tissue protection and thus produce inflammation. During many inflammatory diseases, tissue hypoxia will occur due to increased local oxygen consumption and tissue ischemia, so hypoxia is closely related to inflammation. HIFs are central to mediating these responses during hypoxia or inflammation (Bowser et al. 2017 ). It is now well established that inflammatory and hypoxic conditions increase extracellular Adenosine triphosphate (ATP) and Adenosine diphosphate (ADP) release, and that HIF-1α drives adenosine signaling molecules, ATP and AMP, which are composed of endothelial cell surface enzymes, extracellular adenosine triphosphate bisphosphatase (CD39, which metabolizes ATP to AMP), and 5 '-extracellular nucleotidase (CD73, Metabolize AMP to adenosine) metabolism (Eltzschig et al. 2006 ), and adenosine produced in this way can activate endothelial adenosine receptors. This significantly increases extracellular adenosine levels, enabling further tissue adaptation (Eltzschig 2013 ). This mechanism by which HIF regulates extracellular adenosine levels may be related to the enhancement of nucleotide metabolism by Roxadustat. HIFs drive the increase of extracellular adenosine levels, and extracellular adenosine signaling plays an important role in reducing hypoxia-induced tissue damage and inflammation. Extracellular adenosine receptors (ARs) include A1AR, A2AAR, A2BAR and A3AR, which have protective effects on inflammation in different organs. A large number of literatures has demonstrated that the effects mediated by the four subtypes of ARs have a protective effect on the heart and play an intentional role in myocardial reperfusion injury in a variety of species (McIntosh and Lasley 2012 ). Intravenous administration of adenosine activates the receptor A1AR to slow the heart rate for the treatment of supraventricular tachycardia (Koeppen, Eckle, and Eltzschig 2009 ). It is generally believed that the activation of A1AR before ischemia has a protective effect on the heart. Activation of adenosine receptor A2AAR on T or B lymphocytes after coronary occlusion and reperfusion reduces the size of myocardial infarction (Yang et al. 2005 ) and protects the heart both before and after ischemia and during reperfusion. Activation of A3AR in bone marrow derived cells inhibits the inflammatory response produced by neutrophils, which can reduce myocardial ischemia and reperfusion injury (Ge et al. 2010 ). A large amount of evidence has shown that A3AR can protect cardiac tissues before ischemia and during reperfusion. Myocardial ischemia is associated with insufficient oxygen supply and demand. Specific protein-1 (SP-1) induces CD39, HIF-1α induces CD73 and adenosine-induced receptor A2BAR, which can adapt the heart tissue to ischemia and treat myocardial ischemia and reperfusion injury (Eltzschig, Bonney, and Eckle 2013 ). Although ARs protects the heart before ischemia and during reperfusion, the mechanism of action is not fully understood. Certainly, administration of adenosine or adenosine receptor antagonists that inhibit oxygen sensor compounds such as PHDs, thereby preventing HIF-1α hydroxylation and leading to HIF stabilization, is an attractive therapeutic approach to reduce myocardial injury. Inflammatory bowel disease is characterized by excessive intestinal inflammation and deep intestinal hypoxia, and pharmacological compounds that stabilize HIFs provide effective protection during intestinal inflammation. During inflammation, ATP is converted to adenosine by cell-surface extracellular nucleotidase, extracellular CD39, and extracellular CD73. Adenosine signals through transmembrane adenosine receptors and is terminated by re-entry into the cell through the activity of balanced or concentrated nucleoside transporters (ENTs, CNTs) or adenosine deaminase. A2BR is the major adenosine receptor expressed on intestinal epithelial cells, whereas A2AR is expressed by most immune cells (Bowser, Phan, and Eltzschig 2018 ). Increased HIF-1α by PHD inhibitors or increased adenosine signaling by adenosine receptor agonists (e.g., A2AR, A2BR, and possibly A3R) could provide therapeutic benefits for patients with inflammatory bowel disease, intestinal ischemia/reperfusion injury and colon cancer. Acute lung injury is caused by lung damage or acute infection, and similar to inflammatory bowel disease, patients may benefit from therapeutic strategies that increase HIF stability and adenosine signaling, particularly those targeting the lungs. Termination of lung adenosine signaling is primarily mediated by ENT2, which activates the A2BAR adenosine receptor in the alveolar epithelium to protect lung tissue during acute lung injury (Eckle et al. 2013 ). During operation, organ injuries such as myocardial infarction, acute kidney injury and acute intestinal injury will occur. Hypoxia signal induces HIFs stability and promotes the body to produce hypoxia adaptive response. Therefore, regulating HIFs to make it stable may have a profound impact on organ injury during operation. Conceptually, there are two pathways to target HIF stabilization. First, drugs that promote HIFs stabilization, mainly by inhibiting prolyl hydroxylase, such as HIF-PHI drugs such as Roxadustat. Second, direct activation of HIF target genes, such as adenosine receptors. In conclusion, Roxadustat can increase RBC and Hb content in blood, reduce the expression of hypoxemia and inflammatory factors, reduce oxidative stress injury and has pharmacological effects against hypoxic injury under high altitude conditions. Roxadustat is expected to be a feasible anti-altitude hypoxia drug and provide evidence for further clinical application. Abbreviations ROS Reactive oxygen species RBC Erythrocyte Content HACE High-altitude cerebral edoema HAPE High-altitude pulmonary edoema HIF-PHI Hypoxia-Inducible Factor-proline Hydroxylase Inhibitor HIF Hypoxic Inducible Factor PHD Proline Hydroxylase EPO Erythropoietin SOD Superoxide Dismutase GSH Glutataione IL-6 Interleukin-6 IFN-γ Interferon-γ TNF-α Tumor necrosis Factor-α CMC-Na Carboxymethylcellulose Sodium SatO2 Oxygen Saturation PaO2 Oxygen Partial Pressure Hct Hematocrit Hb Hemoglobin HB Hemoglobin Content MCV Mean Erythrocyte Volume ODD Oxygen-dependent degradation domain ATP Adenosine triphosphate ADP Adenosine diphosphate CD39 Adenosine triphosphate bisphosphatase CD73 Adenosine triphosphate bisphosphatase ARs Adenosine receptors SP-1 Specific protein-1 Declarations Ethics Approval This study was approved by the Scientific Research Management Ethics Committee of the 940th Hospital of the Joint Logistic Support Force of the People's Liberation Army (Approval No. : 2022KYLL155). Contacts to Participate No human subjects were involved in this study. Contacts to Publish That the work described has not been published before. That its publication has been approved by all co-authors. Author Contribution QG and WL conceived and designed research. QG and XL conducted experiments. RW and AZ contributed new reagents or analytical tools. QG and ZW analyzed data. QG wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used. Funding This work was supported by support from the National Natural Science Foundation of China (Grant No. 82173738) . Competing Interests The authors have no relevant financial or non-financial interests to disclose. About Data Availability Statements All data generated or analysed during this study are included in this published article. References Bowser, J. L., Lee, J. W., Yuan, X., & Eltzschig, H. K. (2017). 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J Mol Cell Cardiol, 49(2), 280–286. doi: 10.1016/j.yjmcc.2010.01.018 Haase, V. H. (2017). HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int, 21 Suppl 1(Suppl 1), S110-s124. doi: 10.1111/hdi.12567 Hou HP, Zhang GP, Gao YH, Li H, Song L, Chen TF, Zhang ZX, and Ye ZG.(2020). Protective effects of salidroside on chronic obstructive pulmonary disease in vitro and its mechanism of antioxidant stress, Chinese Traditional Medicine and Clinical Pharmacology,31(12), 1389–1393. doi: 10.19378/j.issn.1003-9783.2020.12.001 Kaelin, W. G., Jr., & Ratcliffe, P. J. (2008). Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell, 30(4), 393–402. doi: 10.1016/j.molcel.2008.04.009 Kirschner, K. M., Kelterborn, S., Stehr, H., Penzlin, J. L. T., Jacobi, C. L. J., Endesfelder, S.,.. . Sciesielski, L. K. (2022). Adaptation of the Oxygen Sensing System during Lung Development. Oxid Med Cell Longev, 2022, 9714669. doi: 10.1155/2022/9714669 Koeppen, M., Eckle, T., & Eltzschig, H. K. (2009). Selective deletion of the A1 adenosine receptor abolishes heart-rate slowing effects of intravascular adenosine in vivo. PLoS One, 4(8), e6784. doi: 10.1371/journal.pone.0006784 Leaf, D. E., & Goldfarb, D. S. (2007). Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J Appl Physiol (1985), 102(4), 1313–1322. doi: 10.1152/japplphysiol.01572.2005 Long, G., Chen, H., Wu, M., Li, Y., Gao, L., Huang, S.,.. . Xia, W. (2020). Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways. Front Pharmacol, 11, 1191. doi: 10.3389/fphar.2020.01191 McIntosh, V. J., & Lasley, R. D. (2012). Adenosine receptor-mediated cardioprotection: are all 4 subtypes required or redundant? J Cardiovasc Pharmacol Ther, 17(1), 21–33. doi: 10.1177/1074248410396877 Miao, M., Wu, M., Li, Y., Zhang, L., Jin, Q., Fan, J.,.. . Jia, Z. (2022). Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases. Front Pharmacol, 13, 837249. doi: 10.3389/fphar.2022.837249 Wang, B., Zhang, Y. B., Zhang, F., Lin, H., Wang, X., Wan, N.,.. . Yu, J. (2011). On the origin of Tibetans and their genetic basis in adapting high-altitude environments. PLoS One, 6(2), e17002. doi: 10.1371/journal.pone.0017002 Yang, Z., Day, Y. J., Toufektsian, M. C., Ramos, S. I., Marshall, M., Wang, X. Q.,.. . Linden, J. (2005). Infarct-sparing effect of A2A-adenosine receptor activation is due primarily to its action on lymphocytes. Circulation, 111(17), 2190–2197. doi: 10.1161/01.Cir.0000163586.62253.A5 Yasuoka, Y., Izumi, Y., Fukuyama, T., Omiya, H., Pham, T. D., Inoue, H.,.. . Nonoguchi, H. (2022). Effects of Roxadustat on Erythropoietin Production in the Rat Body. Molecules, 27(3). doi: 10.3390/molecules27031119 Zhang, C., Wang, N., Xu, Y., Tan, H.-Y., Li, S., & Feng, Y. (2018). Molecular Mechanisms Involved in Oxidative Stress-Associated Liver Injury Induced by Chinese Herbal Medicine: An Experimental Evidence-Based Literature Review and Network Pharmacology Study. International Journal of Molecular Sciences, 19(9). doi: 10.3390/ijms19092745 Additional Declarations No competing interests reported. Supplementary Files Rawdata.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1920898","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":127398585,"identity":"6ee2c1e7-dacc-4a74-b3e7-0cf6698d280b","order_by":0,"name":"Qianwen Guo","email":"","orcid":"","institution":"The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qianwen","middleName":"","lastName":"Guo","suffix":""},{"id":127398586,"identity":"95e9a1eb-c509-4311-ba93-06aa979b1736","order_by":1,"name":"Xue Li","email":"","orcid":"","institution":"The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xue","middleName":"","lastName":"Li","suffix":""},{"id":127398587,"identity":"c0e99205-e411-4e1b-84bc-e12323901c0f","order_by":2,"name":"Wenbin Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIie3QsQrCMBCA4SuBTGldk0X7CCeFTnkTl3TJ5t6hYEGoi9DVxxB8gcBBp4KPYMEXCLg6WDe3ZnTItwXyH9wBRNE/Yg7Ao1yvGKMpLOEGkkutC3XiFoMTJkZbXe8il0EFDuzp046SGwlAaPQuIOGlVB2xklI3wWD37WLyOHPYdsRLygwmLQUkg2C+6kgUR4EyNAHpRiuRhSZq3kW1tUZJ85FNyC7ZfLHXG+Wh74km3+jlJHe/L7P0/WuzODSKoij6ADp4P7AAC9ZCAAAAAElFTkSuQmCC","orcid":"","institution":"The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Wenbin","middleName":"","lastName":"Li","suffix":""},{"id":127398588,"identity":"7636af2e-9d20-4f6a-ab56-ce85de6c2194","order_by":3,"name":"Rong Wang","email":"","orcid":"","institution":"The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rong","middleName":"","lastName":"Wang","suffix":""},{"id":127398589,"identity":"29bc7e9a-2133-44f5-a6ed-0c2cde0d2cf5","order_by":4,"name":"Anpeng Zhao","email":"","orcid":"","institution":"The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anpeng","middleName":"","lastName":"Zhao","suffix":""},{"id":127398590,"identity":"5e364b8d-051f-4e25-8796-b17775b1e2c5","order_by":5,"name":"Zihan Wang","email":"","orcid":"","institution":"The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zihan","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2022-08-02 09:14:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1920898/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1920898/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":25050113,"identity":"09334136-5875-45d4-b5c2-e655b30cbb0e","added_by":"auto","created_at":"2022-08-10 16:20:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":77832,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of roxadustat on inflammatory factor and EPO in rats plasma. The content of IFN-γ\u003cstrong\u003e(A)\u003c/strong\u003e, IL-6\u003cstrong\u003e(B)\u003c/strong\u003e, TNF-α\u003cstrong\u003e(C)\u003c/strong\u003e and EPO\u003cstrong\u003e(D)\u003c/strong\u003e. Error bars indicate SD (\u003cem\u003en\u003c/em\u003e=6/per group). \u003csup\u003e#\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05, \u003csup\u003e##\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.01 versus normal oxygen group; *\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05, **\u003cem\u003ep\u003c/em\u003e\u0026lt;0.01 versus hypoxic group.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-1920898/v1/619bb4fcee55565e8d7a3e4d.png"},{"id":25050753,"identity":"8fe18990-5c06-4622-b757-feb2380cfb82","added_by":"auto","created_at":"2022-08-10 16:25:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":177050,"visible":true,"origin":"","legend":"\u003cp\u003eThe activity of SOD, the content of MDA\u003cstrong\u003e \u003c/strong\u003eand GSH. Effects of roxadustat on oxidative stress in rats myocardial tissue (A-C). Effects of roxadustat on oxidative stress in rats renal tissue (D-F). Effects of roxadustat on oxidative stress in rats brain tissue (G-I). Effects of roxadustat on oxidative stress in rats lung tissue (J-L). Effects of roxadustat on oxidative stress in rats liver tissue (M-O). Error bars indicate SD (\u003cem\u003en\u003c/em\u003e=6/per group). \u003csup\u003e#\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05, \u003csup\u003e##\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.01 versus normal oxygen group; *\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05, **\u003cem\u003ep\u003c/em\u003e\u0026lt;0.01 versus hypoxic group.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-1920898/v1/ee0d308400256799220fad85.png"},{"id":25050110,"identity":"7d750f00-df4e-48bf-aa25-836ba8a3a47e","added_by":"auto","created_at":"2022-08-10 16:20:20","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":117981,"visible":true,"origin":"","legend":"\u003cp\u003ePathological results of myocardial tissue in rats (HE, 40.0×). Normal oxygen group (A); Hypoxic group (B); Acetazolamide group (C); Roxadustat group (D).\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1920898/v1/0c9ff1fbeb91645408510610.jpg"},{"id":25051138,"identity":"5e51447c-c1ce-4ee1-97dc-43ce23b36f11","added_by":"auto","created_at":"2022-08-10 16:30:20","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":108794,"visible":true,"origin":"","legend":"\u003cp\u003ePathological results of brain tissue in rats (HE, 40.0×). Normal oxygen group (A); Hypoxic group (B); Acetazolamide group (C); Roxadustat group (D).\u0026nbsp;\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1920898/v1/6755c4ec02346383a1fe3175.jpg"},{"id":25050111,"identity":"23db3cf6-b466-480a-aa18-63642eb78ae0","added_by":"auto","created_at":"2022-08-10 16:20:20","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":111969,"visible":true,"origin":"","legend":"\u003cp\u003ePathological results of lung tissue in rats (HE, 40.0×). Normal oxygen group (A); Hypoxic group (B); Acetazolamide group (C); Roxadustat group (D).\u0026nbsp;\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1920898/v1/ba5c7a52c008cd029d9ed2c7.jpg"},{"id":25368398,"identity":"a4a2bed8-2a24-45df-a48d-8f2c35bc507a","added_by":"auto","created_at":"2022-08-18 13:59:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":937495,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1920898/v1/83f31dde-3fb0-4f19-a407-83eaf220a2b4.pdf"},{"id":25050115,"identity":"78752910-1df7-43fc-bc1f-d6fd53582e40","added_by":"auto","created_at":"2022-08-10 16:20:21","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":36132532,"visible":true,"origin":"","legend":"","description":"","filename":"Rawdata.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1920898/v1/4b30b85975f5a9dd663b1a09.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Pharmacodynamic Evaluation of the Protective Effects of Roxadustat Against Hypoxic Injury at High Altitude","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHypoxia rapidly increases the levels of free radicals in cells and whole-body hypoxia overwhelms the reserves of scavengers, leading to the accumulation of reactive oxygen species (ROS), the release of inflammatory factors and injury of red blood cells (RBC), vascular endothelial cells and other tissues, such as lung, brain and heart, and ultimately leading to life-threatening high-altitude cerebral edoema (HACE) or high-altitude pulmonary edoema (HAPE) (Leaf and Goldfarb \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2007\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eRoxadustat, a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI) for the treatment of renal anemia, completed the Phase III clinical trial in China on December 18, 2018, and was approved (Dhillon \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Proline hydroxylase (PHD) is a rate-limiting enzyme for the degradation of the hypoxic inducible factor (HIF), a regulator of erythropoietin (EPO). EPO promotes erythropoiesis (Haase \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). By inhibiting the rate of PHD to degrade HIF, roxadustat stabilizes the expression of HIF protein to promote the expression of EPO (Long et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Deguchi et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2020\u003c/span\u003e. ). Red blood cells are rich in hemoglobin, which plays a crucial role in the oxygen combination, utilization, transportation, and release (Wang et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Under hypoxia conditions, roxadustat can improve hypoxemia and alleviate hypoxia by promoting EPO production and increasing red blood cell and hemoglobin content.\u003c/p\u003e \u003cp\u003eIn the present study, we performed a randomized controlled experimental study based on the experimental animals to evaluate, the anti-hypoxia effect of roxadustat, the pharmacodynamics of roxadustat were preliminarily explored through atmospheric pressure closed hypoxic and acute altitude field hypoxia experiments.\u003c/p\u003e"},{"header":"Material And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAnimals\u003c/h2\u003e \u003cp\u003eA total of 32 male BALB/c mice, weighting 18\u0026ndash;22 g each, were provided by 940th Hospital (SYXK (Military) 2020-0032) for the study. Subsequently, 32 mice were randomly divided into 4 groups (n\u0026thinsp;=\u0026thinsp;8): Control group, roxadustat low-dose group (7.8 mg/kg), medium-dose group (15.6 mg/kg), high-dose group (31.2 mg/kg).\u003c/p\u003e \u003cp\u003eA total of 24 healthy Wistar male rats (weight, 200 g\u0026thinsp;\u0026plusmn;\u0026thinsp;2 g), were purchased from Liaoning Changsheng Biotechnology Co. LTD. (SCXK (Liaoning) 2020-0001). The rats were randomly divided into 4 groups (n\u0026thinsp;=\u0026thinsp;6): Normoxic blank group, hypoxia model group, acetazolamide group (22.5 mg/kg), roxadustat group (10.8 mg/kg).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDrug and reagent\u003c/h2\u003e \u003cp\u003eRoxadustat Capsules (Specification: 20 mg\u0026times;3 tablets, AstraZeneca Pharmaceutical Co. LTD.); Normal Saline (500 ml: 4.5 g, Shijiazhuang Siyao Pharmaceutical Co. LTD. Batch No. 2007122002); Heparin (Shanghai First Biochemical Pharmaceutical Co. LTD.); Acetazolamide (Purity༞98.0%, Shanghai Yuanye Biotechnology Co. LTD. CAS#59-66-5); Rat TNF-α Elisa kit, Rat IL-6 Elisa kit, MDA kit (Nanjing Jicheng Institute of Bioengineering); Rat EPO Elisa kit (Shanghai Jianglai Industrial Limited by Share LTD.); SOD kit (Nanjing Jiancheng Institute of Biological Engineering); GSH Kit (Nanjing Jiancheng Institute of Biological Engineering); 4% Paraformaldehyde (500 ml, Wuhan Xaver Biotechnology Co. LTD.).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAnoxic endurance test under atmospheric pressure\u003c/h2\u003e \u003cp\u003e32 BALB/c mice were administrated intragastric for one week, and the equivalent dose of roxadustat was 15.6 mg/kg by body surface area conversion method (Conversion coefficient of mice = (Body size coefficient mouse \u0026times;W\u003csup\u003e2/3\u003c/sup\u003e \u003csub\u003emouse\u003c/sub\u003e)/(Body size coefficient man \u0026times;W\u003csup\u003e2/3\u003c/sup\u003e \u003csub\u003ehuman\u003c/sub\u003e), according to the clinical dose of human. Roxadustat low dose, medium dose and high dose groups were given 0.5 times, 1 time and 2 times of the equivalent dose, namely 7.8 mg/kg, 15.6 mg/kg and 31.2 mg/kg, dissolved in normal saline and assisted with 0.5% carboxymethylcellulose sodium (CMC-Na) and 0.1% tween-80. The control group was given the same amount of solvent once every two days. The experiment was started 1 h after the fourth administration. 40 mice were put into 250 ml jar (put filter paper and sodium lime into the bottle in advance, smear vaseline evenly on the bottle mouth and stopper), per mouse into the bottle and screw down the lid as began to anoxia time, stop breathing in mice, legs no longer tic as a time of death, statistics the survival time of mice and prolong the rate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eField anoxia experiment at high altitude\u003c/h2\u003e \u003cp\u003eRats from Lanzhou to gavage in advance to medicine 3 times, roxadustat group and hypoxia model group 1 time two day, acetazolamide group 2 times one day, the fourth day morning by constant temperature after dosing van rats to Xining airport, and then accelerated to Yushu Tibetan autonomous prefecture in Qinghai province high altitude field laboratory (33.1 \u0026deg;N, 96.7 \u0026deg;E, at an altitude of 4,010 m. The temperature was 10 ℃, the humidity was 80%), and the water was freely supplemented with jelly on the way. After arriving in Yushu, the rats underwent acute hypoxia for 3 days. On the fourth day, blood was collected from the ocular venous plexus, anaesthesia with chloral hydrate, and blood was collected from the abdominal aorta. The heart, liver, brain, lung, and kidney tissues were collected for index determination.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eDetermination of blood routine index\u003c/h2\u003e \u003cp\u003eOne hour after administration, 0.5 ml of orbital venous plexus blood was collected from the centrifuge tube rinsed with heparin, and immediately put into an automatic hematology analyzer to measure relevant indexes of blood routine.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMeasure inflammatory factor index and erythropoietin\u003c/h2\u003e \u003cp\u003e1 h after administration, 0.5 ml of orbital venous blood was collected in a heparin-rinsed centrifuge tube, centrifuged at room temperature at 3,500 r/min for 10 min, and the supernatant was taken and stored in a liquid nitrogen tank, which was transported to Lanzhou in strict accordance with IL-6, IFN-γ, TNF-α and EPO ELISA kit for operation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eMeasure blood gas index\u003c/h2\u003e \u003cp\u003eAfter anesthesia, the abdominal cavity of rats was opened and 0.5 ml of abdominal aortic blood was collected, which was immediately determined by a blood gas analyzer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eChanges in oxidative stress indicators\u003c/h2\u003e \u003cp\u003eAfter collecting the the abdominal aortic blood from rats, the myocardium, liver, brain, lung, and kidney tissues were extracted completely on ice. The blood was washed in pre-cooled normal saline, and the water was drained by filter paper before being stored in liquid nitrogen tanks. During the determination, the tissues were weighed and added with pre-cooled normal saline (M:V\u0026thinsp;=\u0026thinsp;1:9) in proportion, fully ground in a homogenizer, centrifuged at 4 ℃ at a speed of 4,000 r/min for 10 min, and the supernatant was taken to obtain 10% tissue homogenate. The homogenate was determined in strict accordance with the instructions of the SOD, MDA and GSH kit.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eHE dyed\u003c/h2\u003e \u003cp\u003eAfter collecting the abdominal aortic blood from rats, the myocardium, liver, brain, lung and kidney tissues of 2 rats in each experimental group were extracted completely on ice. The blood stains were washed in pre-cooled normal saline and immediately fixed in 4% paraformaldehyde. In Lanzhou, the tissues were dehydrated, embedded, sliced, and stained with HE.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSPSS 21.0 software was used for statistical analysis, one-way analysis of variance, and an independent sample T test were used for analysis. The statistical results were expressed by mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, P༜0.05 is a statistical difference.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003eEffect of roxadustat on survival time of mice under atmospheric pressure\u003c/h2\u003e\n\u003cp\u003eCompared with the control group, the survival time of low, medium, and high dose roxadustat groups were significantly prolonged, with an increased rate of 13.73%, 19.05% and 14.15%, respectively. The results indicate that roxadustat can increase the survival time of mice in atmospheric hypoxia, and the effect of medium-dose is the best (Table.1.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable.1\u003c/strong\u003e Effects of different doses of roxadustat on the survival time of mice. Error bars indicate SD (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8/per group \u003cem\u003ex̄\u003c/em\u003e \u0026plusmn;s). Compared with control group, \u003csup\u003e*\u003c/sup\u003ep\u0026lt; 0.05; \u003csup\u003e**\u003c/sup\u003ep\u0026lt; 0.01.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tabb\" border=\"1\"\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGroup\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDose (mg/kg)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSurvival time (min)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIncrease rate\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003econtrol group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e28.77\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow dose roxadustat group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e32.72\u0026thinsp;\u0026plusmn;\u0026thinsp;5.24*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e13.73%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emediumdose roxadustat group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e34.25\u0026thinsp;\u0026plusmn;\u0026thinsp;3.64**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e19.05%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehigh dose roxadustat group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e31.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e32.84\u0026thinsp;\u0026plusmn;\u0026thinsp;3.40*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14.15%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n\u003ch2\u003eEffects of roxadustat on blood gas in field hypoxia rats at high altitude\u003c/h2\u003e\n\u003cp\u003eCompared with normal oxygen group, blood SaO\u003csub\u003e2\u003c/sub\u003e and PaO\u003csub\u003e2\u003c/sub\u003e in the hypoxic group were significantly decreased by 5.81% and 34.49%, respectively (both P\u0026lt;0.01), Hct, pH and Hb contents were significantly increased by 18.00%, 0.68% and 16.31% (all P\u0026lt;0.01) (Table.2.). Compared with the hypoxic group, SaO\u003csub\u003e2\u003c/sub\u003e and PaO\u003csub\u003e2\u003c/sub\u003e in the roxadustat group were significantly increased by 3.21% and 11.56%, respectively (both P\u0026lt;0.01), erythrocyte Hct, pH and Hb contents were significantly decreased by 12.46%, 0.27% and 11.85%, respectively (all P\u0026lt;0.01) (Table.2.). The results indicate that roxadustat can significantly improve the blood gas index of acute altitude hypoxic rats.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable.2\u003c/strong\u003e Comparison of blood gas indexes in each group. Error bars indicate SD (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6/per group \u003cem\u003ex̄\u003c/em\u003e\u0026plusmn;s).Compared with normal oxygen group, \u003csup\u003e#\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05; \u003csup\u003e##\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.01; Compared with anoxic blank group, \u003csup\u003e*\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05; \u003csup\u003e**\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.01.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tabc\" border=\"1\"\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGroup\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSaO2 (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePaO2\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHct (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003epH (mmHg)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHb (g/L)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal oxygen group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e96.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e90.22\u0026thinsp;\u0026plusmn;\u0026thinsp;3.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e35.17\u0026thinsp;\u0026plusmn;\u0026thinsp;1.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e7.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e118.50\u0026thinsp;\u0026plusmn;\u0026thinsp;2.74\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehypoxic group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e91.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.46##\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e59.10\u0026thinsp;\u0026plusmn;\u0026thinsp;1.64##\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e41.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55##\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e7.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01##\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e137.83\u0026thinsp;\u0026plusmn;\u0026thinsp;2.14##\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eacetazolamide group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e91.47\u0026thinsp;\u0026plusmn;\u0026thinsp;1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e64.00\u0026thinsp;\u0026plusmn;\u0026thinsp;2.08**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e36.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e7.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e123.33\u0026thinsp;\u0026plusmn;\u0026thinsp;2.50**\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eroxadustat group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e94.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.72**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e65.93\u0026thinsp;\u0026plusmn;\u0026thinsp;2.84**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e36.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e7.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e121.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84**\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n\u003ch2\u003eEffects of roxadustat on blood routine in field hypoxia rats at high altitude\u003c/h2\u003e\n\u003cp\u003eCompared with normal oxygen group, RBC and Hb in the hypoxic group were significantly decreased by 10.70% and 37.46%, respectively (both P\u0026lt;0.01), MCV was significantly increased by 15.14% (P\u0026lt;0.01) (Table.3.). Compared with the hypoxic group, RBC, Hb, and HCT in the roxadustat group were significantly increased by 8.00%, 7.62% and 5.09%, respectively (all P\u0026lt;0.01) (Table.3.). The results indicate that roxadustat can significantly improve the blood routine indexes of acute altitude hypoxic rats.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable.3\u003c/strong\u003e Comparison of blood routine indexes in each group. Error bars indicate SD (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6/per group \u003cem\u003ex̄\u003c/em\u003e\u0026plusmn;s). Compared with normal oxygen blank group, \u003csup\u003e#\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05; \u003csup\u003e##\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt; 0.01; Compared with anoxic blank group, \u003csup\u003e*\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05; \u003csup\u003e**\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.01.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tabd\" border=\"1\"\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGroup\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRBC (10^6/uL)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHb (mmol/L)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHCT (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMCV (fl)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enormal oxygen group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e8.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e16.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e47.75\u0026thinsp;\u0026plusmn;\u0026thinsp;2.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e51.38\u0026thinsp;\u0026plusmn;\u0026thinsp;1.19\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehypoxic group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e8.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14##\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e10.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24##\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e47.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e59.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.99##\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eacetazolamide group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e8.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e10.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e49.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e60.28\u0026thinsp;\u0026plusmn;\u0026thinsp;1.52\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eroxadustat group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e8.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e10.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e50.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\"\u0026plusmn;\"\u003e\n\u003cp\u003e60.60\u0026thinsp;\u0026plusmn;\u0026thinsp;1.51\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eEffects of roxadustat on plasma inflammatory factors and EPO in field hypoxia rats at high altitude\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter 3 days of hypoxia, the results of plasma inflammatory factors showed that the levels of IFN-\u0026gamma;, IL-6 and TNF-\u0026alpha; in the hypoxia model group were significantly higher than those in the normoxic blank group. Compared with the hypoxia group, the content of IFN-\u0026gamma;, IL-6 and TNF-\u0026alpha; in the roxadustat group significantly decreased by 26.66%, 51.4༅, 42.06༅, and the contents of EPO were significantly increased by 65.44༅ (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n\u003ch2\u003eEffects of roxadustat on oxidative stress in field hypoxia rats at high altitude\u003c/h2\u003e\n\u003cp\u003eAfter 3 days of hypoxia, the results of oxidative stress showed that compared with the normal oxygen group, the SOD activity in renal, lung, and liver tissue in the hypoxia group was significantly decreased (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.D, J and M), and the MDA content in myocardial and lung was significantly increased (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.B and K). The activity of GSH in lung, liver and renal tissue was significantly decreased (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.L, O and F). Compared with the hypoxic group, the SOD activity of brain, lung, liver, and renal tissue in the roxadustat group was significantly increased by 9.64%, 21.61%, 18.68% and 34.98%, respectively (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.G, J, M, and D). MDA content in the myocardial, brain, lung, and liver tissue was significantly decreased by 38.18%, 39.84%, 22.86% and 37.70%, respectively (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.B, H, K, and N). The contents of GSH in myocardial, brain, and renal tissue were significantly increased by 55.84%, 47.03% and 48.80%, respectively (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.C, I and F). The results suggest that roxadustat can ameliorate oxidative stress injury induced by acute altitude hypoxia in rats.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n\u003ch2\u003eEffect of roxadustat on the pathology of field hypoxia rats at high altitude\u003c/h2\u003e\n\u003cp\u003eThe myocardial fibers in the normal oxygen group were neatly arranged and the nuclei were intact. Compared with the normal oxygen group, myocardial fibers in the hypoxic group were disordered and discontinuous, with wavy fiber fracture and inflammatory cell infiltration (FIG.3.). Compared with the hypoxic group, myocardial fibers in the roxadustat group were arranged neatly, inflammation was reduced, and cytoplasm staining was uniform (FIG.3.).\u003c/p\u003e\n\u003cp\u003eThe pyramidal cells in the hippocampus of normal oxygen group were orderly and densely arranged, and the cell structure was normal. Compared with normal oxygen group, pyramidal cells in the hippocampal area of the hypoxic group were disordered and loose, and the cell structure was normal (FIG.4.). Compared with the hypoxic group, the cells in the hippocampal area of the brain tissue of rats in the roxadustat group were arranged neatly and densely, and the cell structure was normal without apparent damage (FIG.4.).\u003c/p\u003e\n\u003cp\u003eIn the normal oxygen group, the alveoli of lung tissue showed thin-walled vacuoles with clear nuclei. Compared with the normal oxygen group, the alveolar wall of the hypoxic group was thickened, with incomplete structure, inflammatory cell infiltration and fibrous hyperplasia (FIG.5.). Compared with the hypoxic group, the alveolar wall of the roxadustat group became thinner, the structure tended to be normal, and the inflammatory cells decreased (FIG.5.).\u003c/p\u003e\n\u003cp\u003eLiver tissue cells in the normal oxygen group were arranged in a cord-like structure around the central venous cavity. Compared with the normal oxygen group, the nucleus of liver tissue in the hypoxic group was vacuolated, punctured necrosis was observed, and the hepatic cord structure was not apparent (FIG.6.). Compared with the hypoxic group, liver tissue cells in the roxadustat group did not show vacuolation and spot necrosis (FIG.6.).\u003c/p\u003e\n\u003cp\u003eThe cell structure of rat kidney tissue in the normal oxygen group was normal. Compared with the normal oxygen group, the renal tubule epithelial cells in the hypoxic group were edema, the lumen was narrow and tortuous, interstitial capillaries were dilated, and red blood cell exudation was observed in the glomeruli (FIG.7.). Compared with the hypoxic group, the renal tubule epithelial cell edema and glomerular erythrocyte exudation of rats in the roxadustat group were reduced (FIG.7.).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis paper verifies roxadustat has the ability of hypoxia tolerance through atmospheric pressure closed hypoxia experiment. The results showed that roxadustat of the high, medium, and low dose could significantly extend the survival time of hypoxia mice, improve the survival ability of mice in hypoxia, and the survival rate of the medium-dose is the highest, consistent with the human equivalent dose, preliminary showed that roxadustat has anti-hypoxia effect.To verify whether roxadustat has the pharmacodynamic effect of protecting rats against hypoxic injury in the field environment at high altitude, this experiment by determination of high altitude on the spot the arterial blood gas in experimental mice, routine blood, plasma inflammatory cytokines, and myocardial, brain, lung, liver, and kidney tissue of oxidative stress index and pathological damage of roxadust at high altitude hypoxia resistance effect is discussed. It is verified that roxadustat has the pharmacodynamics effect of anti-hypoxic injury in the field environment of high altitude.\u003c/p\u003e \u003cp\u003ePrevious studies have shown that roxadustat is mainly used in anaemic diseases. Mengqiu Miao et al's study showed that roxadustat can be potentially used in other non-anaemic diseases (Miao, Wu et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). For example, treatment of acute and chronic kidney diseases, prevention of retinopathy of prematurity, promotion of bone and tendon regeneration, treatment of cardiovascular diseases, treatment of respiratory diseases, neuroprotective effect, application in tissue transplantation, anti-tumor and suppression of SARS-CoV-2. In addition, Karin M. Kirschner et al reported that the HIF-PHD like roxadustat can combat hypoxic partial pressure in the treatment of preterm infant diseases (Kirschner, Kelterborn et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), such as bronchial dysplasia. Yukiko Yasuoka et al. found that roxadustat produced EPO in a number of tissues stimulated by hypoxia by exposing rats to 7% oxygen, specifically regulating EPO production in the kidney (Yasuoka, Izumi et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is essential to better understand the mechanisms how roxadustat is expected to be a viable drug against high altitude hypoxia, hypoxia stimulates a variety of adaptive responses, many mediated via the HIF family of transcriptional complexes, directly up-regulating transcription of genes involved in erythropoiesis, angiogenesis, vasomotor tone, metabolic pathways and processes related to cell multiplication and survival, and indirectly reducing the transcription of genes with other effects.\u003c/p\u003e \u003cp\u003eHypoxia-inducible factor 1 (HIF-1) is composed of two subunits, HIF-1α and HIF-1β. Hif-1α is a major regulator of oxygen homeostasis, and its oxygen-regulated α chain binds to the constitutive aryl hydrocarbon receptor nuclear translocator. Hif-1α chain degradation is due to oxygen-sensitive hydroxylation of either of the two key prolyl residues in the middle of the HIF-1α chain, known as the oxygen-dependent degradation domain (ODD). This is mediated by one of three families of iron and oxogglutarate dependent enzymes known as PHD1-3, PHD is at the heart of the oxygen-sensing pathway leading to HIF-1α activation. In the presence of adequate amounts of oxygen, iron and 2-oxoglutarate prolyl hydroxyl-ation occurs. The hydroxyprolyl residues produced allow binding of the von Hippel\u0026ndash;Lindau E3 ubiquitin ligase complex which causes polyubiquitylation of the HIF-1α chain at a number of lysyl residues which in turn leads to its complete (Kaelin and Ratcliffe \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). Hypoxia inhibits the stability of PHD and HIF-1α. Roxadustat, as a HIF-PHI, can stabilize HIF and inhibit its degradation, reverse the transcription reduction of related genes caused by hypoxia, restore the corresponding physiological response under normoxia, and reduce the damage caused by hypoxia, which proves that Roxadustat does have relevant pharmacological effects. Upon hypoxia, the transcription factor NF-κB is activated by the IKK complex, and IKKβ contains a conserved prolyl hydroxylation site that is homologous to the ODD site of HIF-1α. Hypoxia increases the stability of IKKβ through PHD1 inhibition of IKKβ hydroxylation, and PHD1 directs the separation of NF-κB from its repressor protein, thereby promoting the expression of NF-κB-induced proinflammatory genes. Roxadustat is a HIF-PHI that increases cellular IKKβ activity and NF-κB activity by inhibiting PHD activity. Nf-κβ directly regulates HIF-1α, an event that amplifies the ability of cells to respond to cytokines (Cummins et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2006\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHypoxia can induce adaptive tissue protection and thus produce inflammation. During many inflammatory diseases, tissue hypoxia will occur due to increased local oxygen consumption and tissue ischemia, so hypoxia is closely related to inflammation. HIFs are central to mediating these responses during hypoxia or inflammation (Bowser et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). It is now well established that inflammatory and hypoxic conditions increase extracellular Adenosine triphosphate (ATP) and Adenosine diphosphate (ADP) release, and that HIF-1α drives adenosine signaling molecules, ATP and AMP, which are composed of endothelial cell surface enzymes, extracellular adenosine triphosphate bisphosphatase (CD39, which metabolizes ATP to AMP), and 5 '-extracellular nucleotidase (CD73, Metabolize AMP to adenosine) metabolism (Eltzschig et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2006\u003c/span\u003e), and adenosine produced in this way can activate endothelial adenosine receptors. This significantly increases extracellular adenosine levels, enabling further tissue adaptation (Eltzschig \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). This mechanism by which HIF regulates extracellular adenosine levels may be related to the enhancement of nucleotide metabolism by Roxadustat.\u003c/p\u003e \u003cp\u003eHIFs drive the increase of extracellular adenosine levels, and extracellular adenosine signaling plays an important role in reducing hypoxia-induced tissue damage and inflammation. Extracellular adenosine receptors (ARs) include A1AR, A2AAR, A2BAR and A3AR, which have protective effects on inflammation in different organs. A large number of literatures has demonstrated that the effects mediated by the four subtypes of ARs have a protective effect on the heart and play an intentional role in myocardial reperfusion injury in a variety of species (McIntosh and Lasley \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). Intravenous administration of adenosine activates the receptor A1AR to slow the heart rate for the treatment of supraventricular tachycardia (Koeppen, Eckle, and Eltzschig \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). It is generally believed that the activation of A1AR before ischemia has a protective effect on the heart. Activation of adenosine receptor A2AAR on T or B lymphocytes after coronary occlusion and reperfusion reduces the size of myocardial infarction (Yang et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2005\u003c/span\u003e) and protects the heart both before and after ischemia and during reperfusion. Activation of A3AR in bone marrow derived cells inhibits the inflammatory response produced by neutrophils, which can reduce myocardial ischemia and reperfusion injury (Ge et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). A large amount of evidence has shown that A3AR can protect cardiac tissues before ischemia and during reperfusion. Myocardial ischemia is associated with insufficient oxygen supply and demand. Specific protein-1 (SP-1) induces CD39, HIF-1α induces CD73 and adenosine-induced receptor A2BAR, which can adapt the heart tissue to ischemia and treat myocardial ischemia and reperfusion injury (Eltzschig, Bonney, and Eckle \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Although ARs protects the heart before ischemia and during reperfusion, the mechanism of action is not fully understood. Certainly, administration of adenosine or adenosine receptor antagonists that inhibit oxygen sensor compounds such as PHDs, thereby preventing HIF-1α hydroxylation and leading to HIF stabilization, is an attractive therapeutic approach to reduce myocardial injury.\u003c/p\u003e \u003cp\u003eInflammatory bowel disease is characterized by excessive intestinal inflammation and deep intestinal hypoxia, and pharmacological compounds that stabilize HIFs provide effective protection during intestinal inflammation. During inflammation, ATP is converted to adenosine by cell-surface extracellular nucleotidase, extracellular CD39, and extracellular CD73. Adenosine signals through transmembrane adenosine receptors and is terminated by re-entry into the cell through the activity of balanced or concentrated nucleoside transporters (ENTs, CNTs) or adenosine deaminase. A2BR is the major adenosine receptor expressed on intestinal epithelial cells, whereas A2AR is expressed by most immune cells (Bowser, Phan, and Eltzschig \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Increased HIF-1α by PHD inhibitors or increased adenosine signaling by adenosine receptor agonists (e.g., A2AR, A2BR, and possibly A3R) could provide therapeutic benefits for patients with inflammatory bowel disease, intestinal ischemia/reperfusion injury and colon cancer.\u003c/p\u003e \u003cp\u003eAcute lung injury is caused by lung damage or acute infection, and similar to inflammatory bowel disease, patients may benefit from therapeutic strategies that increase HIF stability and adenosine signaling, particularly those targeting the lungs. Termination of lung adenosine signaling is primarily mediated by ENT2, which activates the A2BAR adenosine receptor in the alveolar epithelium to protect lung tissue during acute lung injury (Eckle et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). During operation, organ injuries such as myocardial infarction, acute kidney injury and acute intestinal injury will occur. Hypoxia signal induces HIFs stability and promotes the body to produce hypoxia adaptive response. Therefore, regulating HIFs to make it stable may have a profound impact on organ injury during operation.\u003c/p\u003e \u003cp\u003eConceptually, there are two pathways to target HIF stabilization. First, drugs that promote HIFs stabilization, mainly by inhibiting prolyl hydroxylase, such as HIF-PHI drugs such as Roxadustat. Second, direct activation of HIF target genes, such as adenosine receptors. In conclusion, Roxadustat can increase RBC and Hb content in blood, reduce the expression of hypoxemia and inflammatory factors, reduce oxidative stress injury and has pharmacological effects against hypoxic injury under high altitude conditions. Roxadustat is expected to be a feasible anti-altitude hypoxia drug and provide evidence for further clinical application.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eROS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eReactive oxygen species\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eRBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eErythrocyte Content\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eHACE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eHigh-altitude cerebral edoema\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eHAPE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eHigh-altitude pulmonary edoema\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eHIF-PHI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eHypoxia-Inducible Factor-proline Hydroxylase Inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eHIF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eHypoxic Inducible Factor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003ePHD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eProline Hydroxylase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eEPO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eErythropoietin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eSOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eSuperoxide Dismutase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eGSH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eGlutataione\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eIL-6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eInterleukin-6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eIFN-\u0026gamma;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eInterferon-\u0026gamma;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eTNF-\u0026alpha;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eTumor necrosis Factor-\u0026alpha;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eCMC-Na\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eCarboxymethylcellulose Sodium\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eSatO2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eOxygen Saturation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003ePaO2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eOxygen Partial Pressure\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eHct\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eHematocrit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eHb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eHemoglobin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eHB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eHemoglobin Content\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eMCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eMean Erythrocyte Volume\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eODD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eOxygen-dependent degradation domain\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eATP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eAdenosine triphosphate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eADP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eAdenosine diphosphate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eCD39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eAdenosine triphosphate bisphosphatase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eCD73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eAdenosine triphosphate bisphosphatase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eARs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eAdenosine receptors\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"16.161616161616163%\"\u003e\n \u003cp\u003eSP-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"83.83838383838383%\"\u003e\n \u003cp\u003eSpecific protein-1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval\u0026nbsp;\u003c/strong\u003eThis study was approved by the Scientific Research Management Ethics Committee of the 940th Hospital of the Joint Logistic Support Force of the People\u0026apos;s Liberation Army (Approval No. : 2022KYLL155).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContacts to Participate\u003c/strong\u003e No human subjects were involved in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContacts to Publish\u0026nbsp;\u003c/strong\u003eThat the work described has not been published before. That its publication has been approved by all co-authors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e QG and WL conceived and designed research. QG and XL conducted experiments. RW and AZ contributed new reagents or analytical tools. QG and ZW analyzed data.\u0026nbsp;QG\u0026nbsp;wrote the manuscript. All authors read and approved the manuscript.\u0026nbsp;The authors declare that all data were generated in-house and that no paper mill was used.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eThis work was supported by support from the National Natural Science Foundation of China (Grant No. 82173738) .\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e The authors have no relevant financial or non-financial interests to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbout Data Availability Statements\u003c/strong\u003e All data generated or analysed during this study are included in this published article.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBowser, J. L., Lee, J. W., Yuan, X., \u0026amp; Eltzschig, H. K. (2017). The hypoxia-adenosine link during inflammation. 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International Journal of Molecular Sciences, 19(9). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/ijms19092745\u003c/span\u003e\u003cspan address=\"10.3390/ijms19092745\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Roxadustat, High Altitude, Hypoxia, Pharmacodynamics, Erythrocyte. ","lastPublishedDoi":"10.21203/rs.3.rs-1920898/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1920898/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives: \u003c/strong\u003eTo explore the protective effects of roxadustat on hypoxia damage in the fast access to high altitude. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003cem\u003e \u003c/em\u003e\u003c/strong\u003eBALB/C mice were randomly divided into control, roxadustat-7.8 mg/kg, roxadustat-15.6 mg/kg and roxadustat-31.2 mg/kg groups. The anti-hypoxic effectiveness of roxadustat in an optimal dose was evaluated by atmospheric pressure closed hypoxic experiment. Wistar rats were randomly divided into normal pressure, hypoxia model, acetazolamide and roxadustat groups to evaluate the protective effects against hypoxic damage. Animal blood was collected for arterial blood-gas analysis, cytokines detection, oxidative stress indicators, and their organs were harvested for pathological examination.\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003cem\u003e \u003c/em\u003e\u003c/strong\u003eCompared with the control group, the survival time of mice were significantly prolonged in all groups. The time prolongation rate of the medium dose was 19.05%, which was the best dose. Compared with the hypoxia model group, the blood SatO\u003csub\u003e2\u003c/sub\u003e and PaO\u003csub\u003e2\u003c/sub\u003e in the roxadustat group were significantly increased; Erythrocyte content, hemoglobin content and hematocrit were significantly increased; Plasma levels of IL-6, TNF-α and IFN-γ were significantly decreased; MDA content in the myocardial, brain, lung and liver tissue were significantly decreased, SOD activity and GSH content in the tissue were significantly increased. The results of HE staining indicated that roxadustat could significantly improve the damage of heart, brain, lung, liver and kidney tissue after hypoxia in rats. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConlusions:\u003cem\u003e \u003c/em\u003e\u003c/strong\u003eRoxadustat can significantly prevent hypoxia-induced tissue damage, oxidative stress and inflammatory response indicating that roxadustat can obviously improve the adaptation to high-altitude exposure.\u003c/p\u003e","manuscriptTitle":"A Pharmacodynamic Evaluation of the Protective Effects of Roxadustat Against Hypoxic Injury at High Altitude","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-08-10 16:20:18","doi":"10.21203/rs.3.rs-1920898/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f4e61f24-a9f4-4b28-9c9a-d9df7598f7e0","owner":[],"postedDate":"August 10th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-08-18T13:59:20+00:00","versionOfRecord":[],"versionCreatedAt":"2022-08-10 16:20:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1920898","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1920898","identity":"rs-1920898","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}