Cited by 313Erythropoietin and Anemia TreatmentCancer, Hypoxia, and MetabolismAcute Kidney Injury Research

The DOI matches its Crossref record; 255 of the 255 references it cites were found in a registry or an index.

Mechanisms of hypoxia signalling: new implications for nephrology

Schödel, Johannes, Ratcliffe, Peter J.·2019·Nature Reviews Nephrology

Open this paper in CoChat — free account

Abstract

Studies of the regulation of erythropoietin (EPO) production by the liver and kidneys, one of the classical physiological responses to hypoxia, led to the discovery of human oxygen-sensing mechanisms, which are now being targeted therapeutically. The oxygen-sensitive signal is generated by 2-oxoglutarate-dependent dioxygenases that deploy molecular oxygen as a co-substrate to catalyse the post-translational hydroxylation of specific prolyl and asparaginyl residues in hypoxia-inducible factor (HIF), a key transcription factor that regulates transcriptional responses to hypoxia. Hydroxylation of HIF at different sites promotes both its degradation and inactivation. Under hypoxic conditions, these processes are suppressed, enabling HIF to escape destruction and form active transcriptional complexes at thousands of loci across the human genome. Accordingly, HIF prolyl hydroxylase inhibitors stabilize HIF and stimulate expression of HIF target genes, including the EPO gene. These molecules activate endogenous EPO gene expression in diseased kidneys and are being developed, or are already in clinical use, for the treatment of renal anaemia. In this Review, we summarize information on the molecular circuitry of hypoxia signalling pathways underlying these new treatments and highlight some of the outstanding questions relevant to their clinical use.

Integrity signals

Registry

Crossref · 10.1038/s41581-019-0182-z

Cites

255 of 255 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212
Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O 2 -Regulated Prolyl Hydroxylation
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
Self-citation
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735
Hypoxia-inducible factors in physiology and medicine
Semenza, G. L. (2012) · Cell · doi:10.1016/j.cell.2012.01.021 · Cited by 3,645
C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333
Self-citation
A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation
Semenza, G. L., & Wang, G. L. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.12.5447 · Cited by 2,617
A conserved family of prolyl-4-hydroxylases that modify HIF
Bruick, R. K., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1066373 · Cited by 2,549
Regulation of hypoxia-inducible factor 1α is mediated by an O 2 -dependent degradation domain via the ubiquitin-proteasome pathway
Huang, L. E., Gu, J., Schau, M., & Bunn, H. F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.7987 · Cited by 2,113
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068
Self-citation

Show all 255 references

Research works printed but not linked: 2

Viault, F. Sur l'augmentation considerable du nombre des globules rouges dans le sang chez les habitants des hauts plateaux de l'Amerique du Sud. Comptes Rendus Academie Sciences Paris 111, 917–918 (1890).
Cockman, M. E. et al. Lack of activity of recombinant HIF prolyl hydroxylases (PHDs) on reported non-HIF substrates. e-Life (in the press).

Sorted by citations

Inflammation in obesity, diabetes, and related disorders
Rohm, T. V., Meier, D. T., Olefsky, J. M., & Donath, M. Y. (2022) · Immunity · doi:10.1016/j.immuni.2021.12.013 · Cited by 2,066
Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs
Cirino, G., Szabó, C., & Papapetropoulos, A. (2022) · Physiological Reviews · doi:10.1152/physrev.00028.2021 · Cited by 578
The effect of HIF on metabolism and immunity
Taylor, C. T., & Scholz, C. C. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00587-8 · Cited by 517
A new perspective on NAFLD: Focusing on lipid droplets
Scorletti, E., & Carr, R. M. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.11.009 · Cited by 394
Chronic tissue inflammation and metabolic diseasePreprint
Lee, Y. S., & Olefsky, J. M. (2021) · Genes & Development · doi:10.1101/gad.346312.120 · Cited by 356
“The mechanisms by which intracellular oxygen levels regulate HIF-1α have been well described and occur mainly at the protein level with smaller effects on mRNA expression (Ivan and Kaelin 2017; Schödel and Ratcliffe 2019; Semenza 2019).”
Background
Kidney physiology and susceptibility to acute kidney injury: implications for renoprotection
Scholz, H., Boivin, F. J., Schmidt-Ott, K. M., Bachmann, S., Eckardt, K., Scholl, U. I., & Persson, P. B. (2021) · Nature Reviews Nephrology · doi:10.1038/s41581-021-00394-7 · Cited by 328
Medical Conditions and High-Altitude Travel
Luks, A. M., & Hackett, P. H. (2022) · New England Journal of Medicine · doi:10.1056/nejmra2104829 · Cited by 226
Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference
Babitt, J. L., Eisenga, M. F., Haase, V. H., Kshirsagar, A. V., Levin, A., Locatelli, F., Małyszko, J., Swinkels, D. W., Tarng, D., Cheung, M., et al. (2021) · Kidney International · doi:10.1016/j.kint.2021.03.020 · Cited by 222
“188 Although phase 2 and 3 clinical studies have suggested that HIF-PHIs may be ef ﬁ ca-cious in patients with CKD irrespective of baseline C-reactive protein levels (Table 7), 150,157,177,178,189 overtly in ﬂ amed patients were excluded from most trials.”
Background
Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis
Eckardt, K., Agarwal, R., Aswad, A., Awad, A., Block, G. A., Bacci, M. R., Farag, Y. M. K., Fishbane, S. N., Hubert, H., Jardine, A. G., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2025956 · Cited by 222
Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression
Wilson, P. C., Muto, Y., Wu, H., Karihaloo, A. K., Waikar, S. S., & Humphreys, B. D. (2022) · Nature Communications · doi:10.1038/s41467-022-32972-z · Cited by 193
Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease
Haase, V. H. (2021) · Kidney International Supplements · doi:10.1016/j.kisu.2020.12.002 · Cited by 200
“HIF-PHD inhibitors (HIF-PHIs) are a new class of drugs that activate HIF transcription factors and have broad therapeutic potential in clinical medicine.(11) As anemia therapy, HIF-PHIs promote erythropoiesis primarily through increased endogenous EPO production and modulation of iron metabolism.”
Background
Hypoxia and chronic kidney disease
Wang, B., Li, Z., Zhang, Y., Wen, Y., Gao, Y.-M., & Liu, B. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103942 · Cited by 181
Novel anemia therapies in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Ku, E., Vecchio, L. D., Eckardt, K., Haase, V. H., Johansen, K. L., Nangaku, M., Tangri, N., Waikar, S. S., Więcek, A., Cheung, M., et al. (2023) · Kidney International · doi:10.1016/j.kint.2023.05.009 · Cited by 162
Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications
Shi, R., Liao, C., & Zhang, Q. H. (2021) · Cells · doi:10.3390/cells10030678 · Cited by 151
“In canonical HIF signaling, hypoxia leads to the stabilization of the labile protein HIF-1α or HIF-2α which complexes with HIF-β (or ARNT), forming heterodimer HIF-1 or HIF-2 that binds to DNA at hypoxia-response elements (HREs) [11].”
Background
Prolyl and lysyl hydroxylases in collagen synthesis
Salo, A. M., & Myllyharju, J. (2020) · Experimental Dermatology · doi:10.1111/exd.14197 · Cited by 144
“[37,40-43] Several HIF P4H inhibitors are currently in clinical trials [44-46] to treat severe anaemia of chronic kidney diseases and the first one (Roxadustat, FibroGen Inc) was approved in China in 2018, Japan in 2019 and the approval processes in the USA and Europe are ongoing.”
Background
Redox signaling at the crossroads of human health and disease
Zuo, J., Zhang, Z., Luo, M., Zhou, L., Nice, E. C., Zhang, W., Wang, C., & Huang, C. (2022) · MedComm · doi:10.1002/mco2.127 · Cited by 123
Hypoxia signaling in cancer: Implications for therapeutic interventions
Zhuang, Y., Liu, K., He, Q., Gu, X., Jiang, C., & Wu, J. (2023) · MedComm · doi:10.1002/mco2.203 · Cited by 119
The role of HIF proteins in maintaining the metabolic health of the intervertebral disc
Silagi, E. S., Schipani, E., Shapiro, I. M., & Risbud, M. V. (2021) · Nature Reviews Rheumatology · doi:10.1038/s41584-021-00621-2 · Cited by 110
The ubiquitin codes in cellular stress responses
Sheng, X., Xia, Z., Yang, H., & Hu, R. (2023) · Protein & Cell · doi:10.1093/procel/pwad045 · Cited by 117
“…hypoxia, PHDs show a decreased activity to catalyze HIF-α hydroxylation as available molecular oxygen is not enough, which leads to reduced interaction between HIF-α and VHL complex, therefore inhibiting HIF-α ubiquitination and promoting HIF accumulation in nucleus (Schödel and Ratcliffe 2019).”
BackgroundMethod
Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis
Foglia, B., Novo, E., Protopapa, F., Maggiora, M., Bocca, C., Cannito, S., & Parola, M. (2021) · Cells · doi:10.3390/cells10071764 · Cited by 102
Mitochondria bridge HIF signaling and ferroptosis blockage in acute kidney injury
Li, W., Xiang, Z., Xing, Y., Shen, L., & Shi, S. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04770-4 · Cited by 90
“FIH activity is inhibited at lower oxygen concentrations than PHDs, which thus provides a hierarchic adaptive mechanism to oxygen tension [4].”
BackgroundInfluential
Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis
Watts, D., Gaete, D., Rodriguez, D., Hoogewijs, D., Rauner, M., Sormendi, S., & Wielockx, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218131 · Cited by 90
Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance
Shang, T., Jia, Z., Li, J., Cao, H., Xu, H., Cong, L., Ma, D., Wang, X., & Liu, J. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-025-01684-4 · Cited by 93
“This stabilized form then binds to HIF-β subunits to form heterodimers that regulate gene expression by binding to hypoxia response elements (HREs) on DNA [26].”
Metabolic regulation of neurodifferentiation in the adult brain
Maffezzini, C., Calvo‐Garrido, J., Wredenberg, A., & Freyer, C. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03430-9 · Cited by 86
NRF2 and Hypoxia-Inducible Factors: Key Players in the Redox Control of Systemic Iron Homeostasis
Duarte, T. L., Talbot, N. P., & Drakesmith, H. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8148 · Cited by 77
“…pathway and hence the key regulators of erythropoiesis has fueled the development of a variety of PHD inhibitors that stabilize HIF and stimulate the expression of HIF-target genes, including EPO, for treatment of diseases, including renal anemia, ischemic stroke, and wound healing (34, 99, 135).”
Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis
Zhou, W., Šimić, P., Zhou, I. Y., Caravan, P. D., Parada, X. F. V., Wen, D., Washington, O. L., Shvedova, M., Pierce, K. A., Clish, C. B., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci164610 · Cited by 76
NCOA4 is Regulated by HIF and Mediates Mobilization of Murine Hepatic Iron Stores After Blood Loss
Li, X., Lozovatsky, L., Sukumaran, A., Gonzalez, L. A., Jain, A., Liu, D., Ayala‐Lopez, N., & Finberg, K. E. (2020) · Blood · doi:10.1182/blood.2020006321 · Cited by 75
Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression
Yang, G., Shi, R., & Zhang, Q. H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218162 · Cited by 78
“HIF-1α mediates the HIF complex’s oxygen sensitivity and interacts with HIF-1β by an authorized Per–ARNT–Sim (PAS) domain [6].”
BackgroundInfluential
Novel Therapeutic Targets for Hypoxia-Related Cardiovascular Diseases: The Role of HIF-1
Liu, M., Galli, G. L. J., Wang, Y., Fan, Q., Wang, Z., Wang, X., & Xiao, W. L. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00774 · Cited by 72
HYPOXIA AND REPRODUCTIVE HEALTH: Hypoxia and ovarian function: follicle development, ovulation, oocyte maturation
Lim, M., Thompson, J. G., & Dunning, K. R. (2020) · Reproduction · doi:10.1530/rep-20-0509 · Cited by 74
Mitochondrial metabolism in neural stem cells and implications for neurodevelopmental and neurodegenerative diseases
Garone, C., Giorgio, F. D., & Carli, S. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05041-w · Cited by 80
“HIF-1 is a transcription factor of the hypoxia signaling pathway organized in two subunits (α and β) that plays a pivotal role in regulating the expression of several glycolytic genes, including HK and PK [52, 84].”
Background
Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis
Brereton, C. J., Yao, L., Davies, E. R., Zhou, Y., Vukmirovic, M., Bell, J. A., Wang, S., Ridley, R. A., Dean, L. S. N., Andriotis, O. G., et al. (2022) · eLife · doi:10.7554/elife.69348 · Cited by 78
Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes
Zheng, X., Narayanan, S., Xu, C., Angelstig, S. E., Grünler, J., Zhao, A., Toro, A. D., Bernardi, L., Mazzone, M., Carmeliet, P., et al. (2022) · eLife · doi:10.7554/elife.70714 · Cited by 69
Proteinuric chronic kidney disease is associated with altered red blood cell lifespan, deformability and metabolism
Bissinger, R., Nemkov, T. G., D’Alessandro, A., Grau, M., Dietz, T., Bohnert, B. N., Essigke, D., Wörn, M., Schaefer, L., Xiao, M., et al. (2021) · Kidney International · doi:10.1016/j.kint.2021.08.024 · Cited by 68
Induced protein degradation for therapeutics: past, present, and future
Yoon, H., Rutter, J. C., Li, Y.-D., & Ebert, B. L. (2024) · Journal of Clinical Investigation · doi:10.1172/jci175265 · Cited by 72
“This, in turn, stimulates erythropoietin synthesis and provides a therapeutic opportunity in certain forms of anemia (131).”
Role of regulation of PD-1 and PD-L1 expression in sepsis
Zhang, T., Yu-Jing, L., & Ma, T. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1029438 · Cited by 75
Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against renal ischemia/reperfusion injury by inhibiting inflammation
Miao, A.-F., Liang, J.-X., Yao, L., Han, J.-L., & Zhou, L.-J. (2021) · Renal Failure · doi:10.1080/0886022x.2021.1915801 · Cited by 67
Nrf2 mediates hypoxia-inducible HIF1α activation in kidney tubular epithelial cells
Potteti, H. R., Noone, P. M., Tamatam, C. R., Ankireddy, A., Noel, S., Rabb, H., & Reddy, S. P. (2021) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00501.2020 · Cited by 64
Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney disease: Advantages and disadvantages
Mima, A. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174583 · Cited by 63
HIF-1α is transcriptionally regulated by NF-κB in acute kidney injury
Li, Z., Ji, J., Wen, Y., Cao, J.-Y., Kharbuja, N., Ni, W., Yin, D., Feng, S., Liu, H., Lv, L., et al. (2021) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00119.2021 · Cited by 61
Comparative Biology of Oxygen Sensing in Plants and Animals
Holdsworth, M. J., & Gibbs, D. J. (2020) · Current Biology · doi:10.1016/j.cub.2020.03.021 · Cited by 56
Histone H3 proline 16 hydroxylation regulates mammalian gene expression
Liu, X., Wang, J., Boyer, J. A., Gong, W., Zhao, S., Xie, L., Wu, Q., Zhang, C., Jain, K., Guo, Y., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01212-x · Cited by 60
Hypoxia-Inducible Factors Signaling in Osteogenesis and Skeletal Repair
Qin, Q., Liu, Y., Yang, Z. L., Aimaijiang, M., Ma, R., Yang, Y., Zhang, Y., & Zhou, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911201 · Cited by 59
Organ cross-talk: molecular mechanisms, biological functions, and therapeutic interventions for diseases
Che, H., Gao, Y., Xu, Y., Xu, H., Eils, R., & Tian, M. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02329-1 · Cited by 57
“179 Additionally, the heart ‒ kidney axis is underscored in various systemic diseases.”
Coassembly of hypoxia-sensitive macrocyclic amphiphiles and extracellular vesicles for targeted kidney injury imaging and therapy
Cheng, Y., Yue, Y., Cao, H., Geng, W., Wang, L.-X., Hu, X., Li, H., Bian, Q., Kong, X., Liu, J., et al. (2021) · Journal of Nanobiotechnology · doi:10.1186/s12951-021-01192-w · Cited by 52
Isomer Engineering of Lepidine-Based Iridophosphors for Far-Red Hypoxia Imaging and Photodynamic Therapy
Tao, P., Lv, Z., Zheng, X.-K., Jiang, H., Liu, S., Wang, H., Wong, W., & Zhao, Q. (2022) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.2c02854 · Cited by 50
The role of hypoxia in stem cell regulation of the central nervous system: From embryonic development to adult proliferation
Li, G., Liu, J., Guan, Y., & Ji, X. (2021) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13754 · Cited by 59
Regulation of chromatin accessibility by hypoxia and HIF
Batie, M., Frost, J., Shakir, D., & Rocha, S. (2022) · Biochemical Journal · doi:10.1042/bcj20220008 · Cited by 48
“HIF is central to transcriptional responses in hypoxia [3 – 6].”
UK kidney association clinical practice guideline: update of anaemia of chronic kidney disease
Bhandari, S., Spencer, S., Oliveira, B., Mikhail, A. I., Brooks, O., Bryant, G., Willicombe, M. K., Baines, R. J., Alldridge, L. C., & Haslam-England, S. (2025) · BMC Nephrology · doi:10.1186/s12882-025-04115-1 · Cited by 51
“Under hypoxic conditions, such as those encountered at high altitudes or in cases of anaemia, HIFs activate the transcription of EPO genes within the kidneys and liver, promoting erythropoiesis to enhance oxygen delivery to tissues [137, 138].”
Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses
Bargiela, D., Cunha, P. P., Veliça, P., Foskolou, I. P., Barbieri, L., Rundqvist, H., & Johnson, R. S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.837669 · Cited by 43
The intricate interplay between HIFs, ROS, and the ubiquitin system in the tumor hypoxic microenvironment
Wang, Y., Liu, X., Huang, W., Liang, J., & Chen, Y. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108303 · Cited by 44
Long‐Term Oxygen Storage Nanosystem for Near‐Infrared Light‐Triggered Oxygen Supplies to Antagonize Hypoxia‐Induced Therapeutic Resistance in Nasopharyngeal Carcinoma
You, Y., Zhao, Z., He, L., Sun, Z., Zhang, D., Shi, C., Cheng, Q., Liu, Y., Luo, L., & Chen, T. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202002369 · Cited by 45
HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis
Jeelani, I., Moon, J.-S., da Cunha, F. F., Nasamran, C. A., Jeon, S., Zhang, X., Bandyopadhyay, G. K., Dobaczewska, K., Mikulski, Z., Hosseini, M., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0284 · Cited by 50
The Asparagine Hydroxylase FIH: A Unique Oxygen Sensor
Volkova, Y. L., Pickel, C., Jucht, A. E., Wenger, R. H., & Scholz, C. C. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0003 · Cited by 43
Role of oxygen and the HIF-pathway in polycystic kidney disease
Buchholz, B., & Eckardt, K. (2020) · Cellular Signalling · doi:10.1016/j.cellsig.2020.109524 · Cited by 46
Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia
Frost, J., Frost, M. G., Batie, M., Jiang, H., & Rocha, S. (2021) · Cancers · doi:10.3390/cancers13020350 · Cited by 44
“Further to HIF isoform expression and activity, evidence points towards pre-established chromatin accessibility and local chromatin environment, including RNA pol II availability, pre-existing promoter enhancer interactions at HREs, and HRE DNA methylation status, as cell-type specificity determinants of hypoxia trans…”
Background
Growing concerns about using hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia
Nakanishi, T., & Kuragano, T. (2024) · Clinical Kidney Journal · doi:10.1093/ckj/sfae051 · Cited by 39
“Regarding HIF-PHDs, HIF-PHIs occupy the AKG binding site and inhibit PHDs, thereby inhibiting O 2 -dependent degradation of HIF-1 α and HIF-2 α , as mentioned above [3 , 44 ].”
Method
Inactivation of EGLN3 hydroxylase facilitates Erk3 degradation via autophagy and impedes lung cancer growth
Jin, Y. H., Pan, Y., Zheng, S., Liu, Y., Xu, J., Peng, Y., Zhang, Z., Wang, Y., Xiong, Y., Xu, L., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02203-2 · Cited by 39
“To assess the EGLN3 hydroxylase activity in KI mice, we analyzed the expression of proteins that were reportedly hydroxylated and destabilized/stabilized by EGLN3, particularly those that play instrumental roles in cancers, such as Erk3, p53 and hypoxia-inducible factor (HIF) 1α [7, 20, 27].”
BackgroundMethodResultInfluential
PGC‐1 alpha regulates mitochondrial biogenesis to ameliorate hypoxia‐inhibited cementoblast mineralization
Wang, H., Wang, X., Ma, L., Huang, X., Peng, Y., Huang, H., Gao, X., Chen, Y., & Cao, Z. (2022) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14872 · Cited by 38
Hypoxia and renal fibrosis
Naas, S., Schiffer, M., & Schödel, J. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00201.2023 · Cited by 46
Self-citation
Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Lin, X., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · BMC Biology · doi:10.1186/s12915-023-01537-x · Cited by 36
“the high-altitude hypobaric hypoxic environment [54].”
The human blood transcriptome exhibits time-of-day-dependent response to hypoxia: Lessons from the highest city in the world
Manella, G., Ezagouri, S., Champigneulle, B., Gaucher, J., Mendelson, M., Lemarié, E., Stauffer, É., Pichon, A., Howe, C. A., Doutreleau, S., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111213 · Cited by 38
“Despite the wide knowledge on the HIF gene program activation (Schodel and Ratcliffe, 2019; Semenza, 2012), the overall transcriptional response induced by hypobaric hypoxia secondary to high-altitude exposure in humans is relatively uncharted (Yasukochi et al.”
Background
Renal Interstitial Fibroblasts Coproduce Erythropoietin and Renin Under Anaemic Conditions
Miyauchi, K., Nakai, T., Saito, S., Yamamoto, T., Sato, K., Kato, K., Nezu, M., Miyazaki, M., Ito, S., Yamamoto, M. P., et al. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2021.103209 · Cited by 35
“Then, data from 137 male patients in CKD stages G3a, G3b, and G4 (as estimated from the glomerular filtration rate [eGFR], which was between 15 and 59 mL/min/1.73 m2 as calculated by the Japanese formula) were selected [17].”
BackgroundInfluential
From acute tubular injury to tubular repair and chronic kidney diseases – KIM-1 as a promising biomarker for predicting renal tubular pathology
Zhang, P. L., & Liu, M. (2025) · Current Research in Physiology · doi:10.1016/j.crphys.2025.100152 · Cited by 34
“It is well known that hypoxia-inducible factors (HIFs) are the master transcription factors regulating hypoxia-associated transcription response (Schodel and Ratcliffe, 2019; Shu et al., 2019).”
Hypoxia activates SUMO-1-HIF-1α signaling pathway to upregulate pro-inflammatory cytokines and permeability in human tonsil epithelial cells
Lin, Y., Wang, M.-J., Xiao, Z., & Jiang, Z. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119432 · Cited by 33
“Hypoxia represents a condition under which the body is deprived of adequate oxygen supply at the tissue level [23].”
Background
Diagnostic Value and Prognostic Significance of Nucleated Red Blood Cells (NRBCs) in Selected Medical Conditions
Pikora, K., Krętowska-Grunwald, A., Krawczuk‐Rybak, M., & Sawicka-Żukowska, M. (2023) · Cells · doi:10.3390/cells12141817 · Cited by 32
FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling
Li, Z., Wang, B., Lv, L., Tang, T., Wen, Y., Cao, J.-Y., Zhu, X., Feng, S., Crowley, S. D., & Liu, B. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00617-4 · Cited by 35
Preclinical Characterization of Vadadustat (AKB-6548), an Oral Small Molecule Hypoxia-Inducible Factor Prolyl-4-Hydroxylase Inhibitor, for the Potential Treatment of Renal Anemia
Zuk, A., Si, Z., Loi, S., Bommegowda, S., Hoivik, D. J., Danthi, S. J., Molnar, G., Csizmadia, V., & Rabinowitz, M. H. (2022) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.122.001126 · Cited by 34
“…HIF degradation is initiated by three iron-containing 2-oxoglutarate (2-OG)-dependent oxygenases known as the prolyl-4-hydroxylase domain (PHD) enzymes PHD1, PHD2, and PHD3 (also known as EGLN2, EGLN1, and EGLN3, respectively) (Epstein et al., 2001; Haase, 2017; Schodel and Ratcliffe, 2019).”
Background
Hypoxia Inducible Factor pathway proteins in high-altitude mammals
Lee, F. S. (2023) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2023.11.002 · Cited by 31
PD-1 immunobiology in glomerulonephritis and renal cell carcinoma
Curran, C. S., & Kopp, J. B. (2021) · BMC Nephrology · doi:10.1186/s12882-021-02257-6 · Cited by 30
“Shifts in oxygen consumption or plasma vitamin D3 (1α-25(OH)2D3) levels disrupt various kidney functions [2, 3] and contribute to the functions of the programmed cell death protein (PD)-1 receptor and its ligands (PD-L1, PD-L2) [4, 5].”
Background
Homocysteine-targeting compounds as a new treatment strategy for diabetic wounds via inhibition of the histone methyltransferase SET7/9
Li, G., Li, D., Wu, C., Li, S., Chen, F., Li, P., Ko, C.-N., Wang, W., Lee, S. M., Lin, L., et al. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00804-1 · Cited by 32
Activation of HIF-1α C-terminal transactivation domain protects against hypoxia-induced kidney injury through hexokinase 2-mediated mitophagy
Li, Z., Ding, L., Ma, R., Zhang, Y., Zhang, Y., Ni, W., Tang, T., Wang, G., Wang, B., Lv, L., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05854-5 · Cited by 30
“Although convincing evidence has indicated that the severity and duration of hypoxia determine the renal prognosis [2, 3], the exact molecular responses of the kidney to hypoxia remain largely enigmatic.”
Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis
Pan, S., Tsai, P., Chou, Y., Chang, Y., Chang, F., Chiu, Y., Chiang, W., Hsu, T., Chen, Y., Chu, T., et al. (2021) · Kidney International · doi:10.1016/j.kint.2021.01.017 · Cited by 31
Tissue-resident memory T cells in the kidney
Asada, N., Ginsberg, P., Gagliani, N., Mittrücker, H., & Panzer, U. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00927-7 · Cited by 33
“Given the hypoxic environment in the kidney [47, 48], it is likely that renal TRM cells also upregulate the expression of hypoxia-responsive genes.”
Background
Fount, fate, features, and function of renal erythropoietin-producing cells
Dahl, S. L., Bapst, A. M., Khodo, S. N., Scholz, C. C., & Wenger, R. H. (2022) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-022-02714-7 · Cited by 30
“The molecular mechanisms governing renal EPO gene expression are well established: under hypoxic conditions, HIF-2α is stabilized and forms together with HIF-β the transcription factor HIF-2 that binds cis-regulatory elements of the EPO gene to enhance its transcription [86, 116].”
Background
Identification of the key DNA damage response genes for predicting immunotherapy and chemotherapy efficacy in lung adenocarcinoma based on bulk, single-cell RNA sequencing, and spatial transcriptomics
Sun, S., Wang, K., Guo, D., Zheng, H., Liu, Y., Shen, H., & Du, J. (2024) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2024.108078 · Cited by 34
Human adaptation to hypoxia in critical illness
McKenna, H., Murray, A. J., & Martín, D. (2020) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00818.2019 · Cited by 30
Detrimental effects of hypoxia on glomerular podocytes
Singh, A., Kolligundla, L. P., Francis, J., & Pasupulati, A. K. (2021) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-021-00788-y · Cited by 29
Cardiac and Kidney Adverse Effects of HIF Prolyl-Hydroxylase Inhibitors for Anemia in Patients With CKD Not Receiving Dialysis: A Systematic Review and Meta-analysis
Zheng, Q., Wang, Y., Yang, H., Sun, L., Zhang, P., Zhang, X., Guo, J., Liu, Y., & Liu, W. J. (2022) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2022.09.014 · Cited by 28
Effects of hypoxia-inducible factor-prolyl hydroxylase inhibitors vs. erythropoiesis-stimulating agents on iron metabolism in non-dialysis-dependent anemic patients with CKD: A network meta-analysis
Yang, J., Xing, J., Zhu, X., Xie, X., Wang, L., & Zhang, X. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1131516 · Cited by 29
Effect of hypoxia-inducible factor-prolyl hydroxylase inhibitors on anemia in patients with CKD: a meta-analysis of randomized controlled trials including 2804 patients
Wang, B., Yin, Q., Han, Y., Wu, M., Li, Z., Tu, Y., Zhou, L., Wei, Q., Liu, H., Tang, R., et al. (2020) · Renal Failure · doi:10.1080/0886022x.2020.1811121 · Cited by 26
“Fourthly, considering a higher dosage of ESA related risk of CV events [52,53] and HIF-PHIs only increase EPO in the physiological level, whether the target Hb level could be upregulated with HIF-PHIs treatment for anemia treatment is yet to be studied.”
Background
Effect of Ashwagandha Withanolides on Muscle Cell Differentiation
Wang, J., Zhang, H., Kaul, A., Li, K., Priyandoko, D., Kaul, S. C., & Wadhwa, R. (2021) · Biomolecules · doi:10.3390/biom11101454 · Cited by 30
“Whereas under normoxia conditions, HIF-1α undergoes hydroxylation and degradation by the proteasome-mediated degradation pathway, hypoxia prevents HIF-1α hydroxylation and degradation [71].”
Background
Sulforaphane Acts Through NFE2L2 to Prevent Hypoxia-Induced Apoptosis in Porcine Granulosa Cells via Activating Antioxidant Defenses and Mitophagy
Zhang, X., Chen, Y., Li, H., Chen, B., Liu, Z., Wu, G., Li, C., Li, R., Cao, Y., Zhou, J., et al. (2022) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c01978 · Cited by 27
Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus
Colli, L. M., Jessop, L., Myers, T. A., Camp, S. Y., Machiela, M. J., Choi, J., Cunha, R., Onabajo, O. O., Mills, G. C., Schmid, V., et al. (2021) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.07.009 · Cited by 27
Salidroside orchestrates metabolic reprogramming by regulating the Hif-1α signalling pathway in acute mountain sickness
Yan, X., Liu, J., Zhu, M., Liu, L., Chen, Y., Zhang, Y., Feng, M., Jia, Z., & Xiao, H. (2021) · Pharmaceutical Biology · doi:10.1080/13880209.2021.1992449 · Cited by 26
“Hif-1 mediates hypoxia and regulates more than 1000 direct transcriptional targets, including metabolic adaptation, angiogenesis, cell cycle and apoptosis (Schodel and Ratcliffe 2019).”
Background
Inflammatory processes involved in NASH-related hepatocellular carcinoma
Cannito, S., Dianzani, U., Parola, M., Albano, E., & Sutti, S. (2023) · Bioscience Reports · doi:10.1042/bsr20221271 · Cited by 29
Molecular regulation and function of FoxO3 in chronic kidney disease
Lin, F. (2020) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000616 · Cited by 24
Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors on iron regulation in non-dialysis-dependent chronic kidney disease patients with anemia: A systematic review and meta-analysis
Li, J., Xie, Q., You, L., Xu, N., & Hao, C. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105256 · Cited by 24
A hydrogel/particle composite with a gradient of oxygen releasing microparticle for concurrent osteogenic and chondrogenic differentiation in a single scaffold
Khorshidi, S., Karimi‐Soflou, R., & Karkhaneh, A. (2021) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2021.112007 · Cited by 25
Hypoxic Regulation of the Large-Conductance, Calcium and Voltage-Activated Potassium Channel, BK
Ochoa, S. V., Otero, L., Aristizábal-Pachón, A. F., Hinostroza, F., Carvacho, I., & Torres, Y. P. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.780206 · Cited by 25
Renal hypoxia–HIF–PHD–EPO signaling in transition metal nephrotoxicity: friend or foe?
Thévenod, F., Schreiber, T., & Lee, W. (2022) · Archives of Toxicology · doi:10.1007/s00204-022-03285-3 · Cited by 27
“Furthermore, HIFs are involved in renal inflammation and fibrosis (for review see Schodel and Ratcliffe 2019).”
Background
A study of survival strategies for improving acclimatization of lowlanders at high-altitude
Sharma, P., Mohanty, S., & Ahmad, Y. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e14929 · Cited by 30
Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury
Zhang, W., Guo, C., Li, Y., Wang, H., Wang, H., Wang, Y., Wu, T., Wang, H., Cheng, G., Man, J., et al. (2024) · Renal Failure · doi:10.1080/0886022x.2024.2332492 · Cited by 24
“Histologically, renal tubule cells are vulnerable to damage during RIRI, including in the forms of tissue hypoxia and mitochondrial dysfunction [4].”
Background
Mitochondrial Iron Handling and Lipid Peroxidation as Drivers of Ferroptosis
Bucarey, J. L., Casas, M., & Espinosa, A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052232 · Cited by 24
“This signal induces its degradation, which is why HIF α cannot bind to HIF β to form the active transcription factor dimer [21].”
Carbon dioxide-dependent signal transduction in mammalian systems
Phelan, D. E., Mota, C., Lai, C., Kierans, S. J., & Cummins, E. P. (2021) · Interface Focus · doi:10.1098/rsfs.2020.0033 · Cited by 27
Roxadustat for dialysis patients with erythropoietin hypo-responsiveness: a single-center, prospective investigation
Zhou, Y., Chen, X., Zhang, Y., Lou, J., & Yuan, H. (2021) · Internal and Emergency Medicine · doi:10.1007/s11739-021-02738-4 · Cited by 24
DNA demethylase ALKBH1 promotes adipogenic differentiation via regulation of HIF-1 signaling
Liu, Y., Chen, Y., Wang, Y., Jiang, S., Lin, W., Wu, Y., Li, Q., Guo, Y., Liu, W., & Yuan, Q. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101499 · Cited by 23
“Oxygen levels are highly heterogeneous among various tissues ranging from 1% to 5%, and controlled concentrations of oxygen help organs function normally (63).”
Background
Hypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II
Liang, X., Potenza, D. M., Brenna, A., Ma, Y., Ren, Z., Cheng, X., Ming, X., & Yang, Z. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.773719 · Cited by 25
Specific inhibition of HIF activity: can peptides lead the way?
Mylonis, I., Chachami, G., & Simos, G. (2021) · Cancers · doi:10.3390/cancers13030410 · Cited by 21
“Under hypoxia, low O2 levels as well as the production of ROS by oxygen-starving mitochondria inhibit hydroxylation and HIFαs escape degradation, accumulate, and translocate inside the nucleus where they assemble with ARNT into transcriptionally active heterodimers (Figure 1) [31].”
Background
Angiotensin-Converting Enzyme Inhibitors Have Adverse Effects in Anti-Angiogenesis Therapy for Hepatocellular Carcinoma
Zhang, S., Cao, M.-Q., Hou, Z., Gu, X.-Y., Chen, Y., Chen, L., Luo, Y., Chen, L.-W., Liu, D., Zhou, H.-Y., et al. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.12.031 · Cited by 22

Authors: Schödel, J., & Ratcliffe, P. J.
Affiliations: Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
The Francis Crick Institute (GB)
Corresponding author: Ratcliffe, Peter J.
ORCID: Schödel, Johannes
Ratcliffe, Peter J.
Venue: Nature Reviews Nephrology
Publisher: Springer Science and Business Media LLC
Published: 2019-09-05
Volume: 15
Issue: 10
Pages: 641-659
ISSN: 1745-8323 (ISSN-L)
1759-5061
1759-507X
DOI: 10.1038/s41581-019-0182-z
OpenAlex: W2971880737
Cited by: 309
References: 255
Citations by year: 2026: 22 · 2025: 36 · 2024: 48 · 2023: 64 · 2022: 53 · 2021: 54 · 2020: 31 · 2019: 1
FWCI: 5.53
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Nephrology (publishedVersion)
PubMed (publishedVersion)
Funders: Wellcome Trust (FC001501)
Cancer Research UK (FC001501)
British Heart Foundation (RG/11/1/28684)
Topics: Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
Keywords: hypoxia signaling, hypoxia-inducible factor, prolyl hydroxylase inhibitors, erythropoietin, anemia of chronic kidney disease, 2-oxoglutarate-dependent dioxygenase, oxygen sensing, kidney disease, HIF target genes
MeSH terms: Animals, Hypoxia, Humans, Kidney, Kidney Diseases, Hypoxia-Inducible Factor 1

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Mechanisms of hypoxia signalling: new implications for nephrology

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks