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18 pages, 667 KiB  
Review
Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors as a New Treatment Option for Anemia in Chronic Kidney Disease
by Piotr Bartnicki
Biomedicines 2024, 12(8), 1884; https://doi.org/10.3390/biomedicines12081884 - 18 Aug 2024
Cited by 3 | Viewed by 4031
Abstract
Anemia plays an important role in chronic kidney disease (CKD) progression because it worsens the quality of life and increases the risk of cardiovascular complications in CKD patients. In such cases, anemia is mainly caused by endogenous erythropoietin (EPO) and iron deficiencies. Therefore, [...] Read more.
Anemia plays an important role in chronic kidney disease (CKD) progression because it worsens the quality of life and increases the risk of cardiovascular complications in CKD patients. In such cases, anemia is mainly caused by endogenous erythropoietin (EPO) and iron deficiencies. Therefore, KDIGO and ERBP guidelines for anemia treatment in CKD patients focus on recombinant EPO and iron supplementation. A recent new treatment option for anemia in CKD patients involves blocking the hypoxia-inducible factor (HIF) system with prolyl hydroxylase inhibitors (PHIs), what causes increasing endogenous EPO production and optimizing the use of iron. Clinical studies have shown that the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) covered in this manuscript—roxadustat, vadadustat, daprodustat, and molidustat—effectively increase hemoglobin (Hb) levels in both non-dialyzed and dialyzed CKD patients. Moreover, these medicines reduce blood lipid levels and do not accelerate CKD progression. However, blockage of the HIF system by HIF-PHIs may be associated with adverse effects such as cardiovascular complications, tumorogenesis, hyperkalemia. and retinopathy. More extensive and long-term clinical trials of HIF-PHIs-based anemia treatment in CKD patients are needed, and their results will indicate whether HIF-PHIs represent an effective and safe alternative to EPO and iron supplementation for anemia treatment in CKD patients. Full article
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10 pages, 930 KiB  
Article
A Prospective Randomized Controlled Clinical Study to Investigate the Efficacy and Safety of Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors in Non-Dialysis Patients with Chronic Heart Failure and Renal Anemia Switched from Continuous Erythropoietin Receptor Activator Treatment
by Akira Sezai, Masanori Abe, Takashi Maruyama, Makoto Taoka, Hisakuni Sekino and Masashi Tanaka
J. Clin. Med. 2024, 13(10), 2764; https://doi.org/10.3390/jcm13102764 - 8 May 2024
Cited by 4 | Viewed by 2842
Abstract
Background/Objectives: Chronic kidney disease (CKD) and anemia are independent prognostic factors for heart failure. In recent years, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have become available for the treatment of renal anemia. This prospective randomized controlled study aimed to investigate the effects of [...] Read more.
Background/Objectives: Chronic kidney disease (CKD) and anemia are independent prognostic factors for heart failure. In recent years, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have become available for the treatment of renal anemia. This prospective randomized controlled study aimed to investigate the effects of switching from a continuous erythropoietin receptor activator (CERA) to one of four HIF-PH inhibitors in patients with chronic heart failure and renal anemia. Methods: Forty patients were randomized by the envelop method to receive treatment with roxadustat, daprodustat, vadadustat, or molidustat. The primary endpoint was the change in the hemoglobin (Hb) level. Secondary endpoints included changes in erythropoietin, changes in free T3, free T4, and thyroid-stimulating hormone (TSH), adverse effects, and drug dose increases and decreases. This study was preregistered in the University Hospital Medical Information Network Clinical Trials Registry (study ID: UMIN000041651). Results: We found no statistically significant difference between Hb levels with HIF-PH inhibitors and CERA, but at month 6, the Hb level was significantly higher with roxadustat than with vadadustat and daprodustat. Erythropoietin decreased significantly after switching to HIF-PH inhibitors. HIF-PH inhibitors had various significant effects on free T3, free T4, and TSH. No adverse events occurred. The doses of some drugs had to be increased or decreased. Conclusions: In patients with heart failure and renal anemia receiving CERA, Hb, NT-ProBNP, and renal function were similar after switching from CERA to HIF-PH inhibitors. The individual HIF-PH inhibitors appear to have different effects on anemia and thyroid function. However, because this was a single-center study with a limited sample size, the efficacy and potential limitations of HIF-PH inhibitors need to be further clarified. Full article
(This article belongs to the Special Issue Current Advances in Optimal Medical Therapy for Heart Failure)
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9 pages, 1717 KiB  
Brief Report
Efficacy of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Clinical Parameters in Patients with Heart Failure
by Mayu Yazaki, Takeru Nabeta, Yu Takigami, Yuko Eda, Teppei Fujita, Yuichiro Iida, Yuki Ikeda, Shunsuke Ishii and Junya Ako
Medicina 2024, 60(1), 84; https://doi.org/10.3390/medicina60010084 - 1 Jan 2024
Cited by 6 | Viewed by 3198
Abstract
Background and Objectives: Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors have been approved as an oral drug for treating anemia in chronic kidney disease (CKD). However, the clinical effect of HIF-PH inhibitors in patients with heart failure (HF) is unclear. Thus, this study investigated [...] Read more.
Background and Objectives: Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors have been approved as an oral drug for treating anemia in chronic kidney disease (CKD). However, the clinical effect of HIF-PH inhibitors in patients with heart failure (HF) is unclear. Thus, this study investigated the effect of HIF-PH inhibitors in patients with HF and CKD. Materials and Methods: Thirteen patients with HF complicated by renal anemia who were started on vadadustat were enrolled. Clinical parameters were compared before and 1 month after vadadustat was started. Results: The mean left ventricular ejection fraction was 49.8 ± 13.9%, and the mean estimated glomerular filtration rate was 29.4 ± 10.6 mL/min/1.73 m2. The hemoglobin level was significantly increased (9.7 ± 1.3 mg/dL vs. 11.3 ± 1.3 mg/dL, p < 0.001), and the N-terminal prohormone of B-type natriuretic peptide was significantly decreased after the introduction of vadadustat [4357 (2651−15182) pg/mL vs. 2367 (1719−9347) pg/mL, p = 0.002]. Furthermore, the number of patients with New York Heart Association functional class ≥ 3 was also decreased after the introduction of vadadustat [8 (61.5%) vs. 1 (7.7%), p = 0.008]. No thromboembolic adverse events or new tumors were observed in any patient during the study period. Conclusions: The introduction of vadadustat in patients with HF complicated by renal anemia led to improvements in anemia and symptoms of HF. Full article
(This article belongs to the Section Cardiology)
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15 pages, 3241 KiB  
Article
Structure–Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors
by Andrey A. Poloznikov, Sergey V. Nikulin, Dmitry M. Hushpulian, Anna Yu. Khristichenko, Andrey I. Osipyants, Andrey F. Asachenko, Olga V. Shurupova, Svyatoslav S. Savin, Sue H. Lee, Irina N. Gaisina, Gregory R. J. Thatcher, Anthony Narciso, Eric P. Chang, Sergey V. Kazakov, Nancy Krucher, Vladimir I. Tishkov, Bobby Thomas and Irina G. Gazaryan
Antioxidants 2022, 11(2), 220; https://doi.org/10.3390/antiox11020220 - 24 Jan 2022
Cited by 4 | Viewed by 5384
Abstract
To evaluate the differences in action of commercially available 2-oxoglutarate mimetics and “branched-tail” oxyquinoline inhibitors of hypoxia-inducible factor prolyl hydroxylase (HIF PHD), the inhibitors’ IC50 values in the activation of HIF1 ODD-luciferase reporter were selected for comparative transcriptomics. Structure–activity relationship and computer [...] Read more.
To evaluate the differences in action of commercially available 2-oxoglutarate mimetics and “branched-tail” oxyquinoline inhibitors of hypoxia-inducible factor prolyl hydroxylase (HIF PHD), the inhibitors’ IC50 values in the activation of HIF1 ODD-luciferase reporter were selected for comparative transcriptomics. Structure–activity relationship and computer modeling for the oxyquinoline series of inhibitors led to the identification of novel inhibitors, which were an order of magnitude more active in the reporter assay than roxadustat and vadadustat. Unexpectedly, 2-methyl-substitution in the oxyquinoline core of the best HIF PHD inhibitor was found to be active in the reporter assay and almost equally effective in the pretreatment paradigm of the oxygen-glucose deprivation in vitro model. Comparative transcriptomic analysis of the signaling pathways induced by HIF PHD inhibitors showed high potency of the two novel oxyquinoline inhibitors (#4896-3249 and #5704-0720) at 2 μM concentrations matching the effect of 30 μM roxadustat and 500 μM dimethyl oxalyl glycine in inducing HIF1 and HIF2-linked pathways. The two oxyquinoline inhibitors exerted the same activation of HIF-triggered glycolytic pathways but opposite effects on signaling pathways linked to alternative substrates of HIF PHD 1 and 3, such as p53, NF-κB, and ATF4. This finding can be interpreted as the specificity of the 2-methyl-substitute variant for HIF PHD2. Full article
(This article belongs to the Special Issue Oxidative Stress in Neurons)
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15 pages, 2510 KiB  
Article
Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α
by Cheng-Bang Jian, Xu-En Yu, Hua-De Gao, Huai-An Chen, Ren-Hua Jheng, Chong-Yan Chen and Hsien-Ming Lee
Nanomaterials 2022, 12(1), 163; https://doi.org/10.3390/nano12010163 - 3 Jan 2022
Cited by 9 | Viewed by 4531
Abstract
Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for [...] Read more.
Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome’s interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors—vadadustat and roxadustat—to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions. Full article
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25 pages, 40235 KiB  
Article
Gene Expression Profile of Human Mesenchymal Stromal Cells Exposed to Hypoxic and Pseudohypoxic Preconditioning—An Analysis by RNA Sequencing
by Katarzyna Zielniok, Anna Burdzinska, Victor Murcia Pienkowski, Agnieszka Koppolu, Malgorzata Rydzanicz, Radoslaw Zagozdzon and Leszek Paczek
Int. J. Mol. Sci. 2021, 22(15), 8160; https://doi.org/10.3390/ijms22158160 - 29 Jul 2021
Cited by 5 | Viewed by 15023
Abstract
Mesenchymal stromal cell (MSC) therapy is making its way into clinical practice, accompanied by research into strategies improving their therapeutic potential. Preconditioning MSCs with hypoxia-inducible factors-α (HIFα) stabilizers is an alternative to hypoxic priming, but there remains insufficient data evaluating its transcriptomic effect. [...] Read more.
Mesenchymal stromal cell (MSC) therapy is making its way into clinical practice, accompanied by research into strategies improving their therapeutic potential. Preconditioning MSCs with hypoxia-inducible factors-α (HIFα) stabilizers is an alternative to hypoxic priming, but there remains insufficient data evaluating its transcriptomic effect. Herein, we determined the gene expression profile of 6 human bone marrow-derived MSCs preconditioned for 6 h in 2% O2 (hypoxia) or with 40 μM Vadadustat, compared to control cells and each other. RNA-Sequencing was performed using the Illumina platform, quality control with FastQC and adapter-trimming with BBDUK2. Transcripts were mapped to the Homo_sapiens. GRCh37 genome and converted to relative expression using Salmon. Differentially expressed genes (DEGs) were generated using DESeq2 while functional enrichment was performed in GSEA and g:Profiler. Comparison of hypoxia versus control resulted in 250 DEGs, Vadadustat versus control 1071, and Vadadustat versus hypoxia 1770. The terms enriched in both phenotypes referred mainly to metabolism, in Vadadustat additionally to vesicular transport, chromatin modifications and interaction with extracellular matrix. Compared with hypoxia, Vadadustat upregulated autophagic, phospholipid metabolism, and TLR cascade genes, downregulated those of cytoskeleton and GG-NER pathway and regulated 74 secretory factor genes. Our results provide valuable insight into the transcriptomic effects of these two methods of MSCs preconditioning. Full article
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18 pages, 3795 KiB  
Article
Vadadustat, a HIF Prolyl Hydroxylase Inhibitor, Improves Immunomodulatory Properties of Human Mesenchymal Stromal Cells
by Katarzyna Zielniok, Anna Burdzinska, Beata Kaleta, Radoslaw Zagozdzon and Leszek Paczek
Cells 2020, 9(11), 2396; https://doi.org/10.3390/cells9112396 - 1 Nov 2020
Cited by 8 | Viewed by 3899
Abstract
The therapeutic potential of mesenchymal stromal cells (MSCs) is largely attributed to their immunomodulatory properties, which can be further improved by hypoxia priming. In this study, we investigated the immunomodulatory properties of MSCs preconditioned with hypoxia-mimetic Vadadustat (AKB-6548, Akebia). Gene expression analysis of [...] Read more.
The therapeutic potential of mesenchymal stromal cells (MSCs) is largely attributed to their immunomodulatory properties, which can be further improved by hypoxia priming. In this study, we investigated the immunomodulatory properties of MSCs preconditioned with hypoxia-mimetic Vadadustat (AKB-6548, Akebia). Gene expression analysis of immunomodulatory factors was performed by real-time polymerase chain reaction (real-time PCR) on RNA isolated from six human bone-marrow derived MSCs populations preconditioned for 6 h with 40 μM Vadadustat compared to control MSCs. The effect of Vadadustat preconditioning on MSCs secretome was determined using Proteome Profiler and Luminex, while their immunomodulatory activity was assessed by mixed lymphocyte reaction (MLR) and Culturex transwell migration assays. Real-time PCR revealed that Vadadustat downregulated genes related to immune system: IL24, IL1B, CXCL8, PDCD1LG1, PDCD1LG2, HIF1A, CCL2 and IL6, and upregulated IL17RD, CCL28 and LEP. Vadadustat caused a marked decrease in the secretion of IL6 (by 51%), HGF (by 47%), CCL7 (MCP3) (by 42%) and CXCL8 (by 40%). Vadadustat potentiated the inhibitory effect of MSCs on the proliferation of alloactivated human peripheral blood mononuclear cells (PBMCs), and reduced monocytes-enriched PBMCs chemotaxis towards the MSCs secretome. Preconditioning with Vadadustat may constitute a valuable approach to improve the therapeutic properties of MSCs. Full article
(This article belongs to the Special Issue Enhancing Mesenchymal Stem Cells (MSCs) for Therapeutic Purposes)
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