Mechanisms of hypoxia signalling: new implications for nephrology
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.
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HIFs are significantly upregulated in many cancer types.
“HIFs are significantly upregulated in many cancer types, and the application of HIF inhibitors as anticancer therapies has captured great interest.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [150]
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Optimal Translational Termination Requires C4 Lysyl Hydroxylation of eRF1
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Self-citationHypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD)
Belibi, F., Zafar, I., Ravichandran, K., Segvic, A. B., Jani, A., Ljubanovic, D. G., & Edelstein, C. L. (2011) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00348.2010 · Cited by 107 · see citing works
Regulation of erythropoietin production is related to proximal tubular function
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Self-citationDistinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin
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<scp>HIF</scp> 3α: the little we know
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Distribution of erythropoietin producing cells in rat kidneys during hypoxic hypoxia
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Self-citationHIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease
Kraus, A., Peters, D. J. M., Klanke, B., Weidemann, A., Willam, C., Schley, G., Kunzelmann, K., Eckardt, K., & Buchholz, B. (2018) · Kidney International · doi:10.1016/j.kint.2018.06.008 · Cited by 94 · see citing works
Chronic Kidney Disease at High Altitude
Luks, A. M., Johnson, R. J., & Swenson, E. R. (2008) · Journal of the American Society of Nephrology · doi:10.1681/asn.2007111199 · Cited by 92 · see citing works
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Evidence for the slow reaction of hypoxia‐inducible factor prolyl hydroxylase 2 with oxygen
Flashman, E., Hoffart, L. M., Hamed, R. B., Bollinger, J. M., Jr., Krebs, C., & Schofield, C. J. (2010) · FEBS Journal · doi:10.1111/j.1742-4658.2010.07804.x · Cited by 90 · see citing works
HIF-Prolyl Hydroxylases in the Rat Kidney
Schödel, J., Klanke, B., Weidemann, A., Buchholz, B., Bernhardt, W. M., Bertog, M., Amann, K., Korbmacher, C., Wiesener, M. S., Warnecke, C., et al. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.080687 · Cited by 89 · see citing works
Self-citationThe Activity of JmjC Histone Lysine Demethylase KDM4A is Highly Sensitive to Oxygen Concentrations
Hancock, R. L., Masson, N., Dunne, K., Flashman, E., & Kawamura, A. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.6b00958 · Cited by 89 · see citing works
VIII. The changes in the breathing and the blood at various high altitudes
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Baumann, B., Hayashida, T., Liang, X., & Schnaper, H. W. (2016) · Kidney International · doi:10.1016/j.kint.2016.05.026 · Cited by 88 · see citing works
An acetate switch regulates stress erythropoiesis
Xu, M., Nagati, J. S., Xie, J., Li, J., Walters, H. C., Moon, Y.-A., Gerard, R. D., Huang, C.-L., Comerford, S. A., Hammer, R. E., et al. (2014) · Nature Medicine · doi:10.1038/nm.3587 · Cited by 87 · see citing works
Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts
Schietke, R. E., Hackenbeck, T., Tran, M. G. B., Günther, R., Klanke, B., Warnecke, C., Knaup, K. X., Shukla, D., Rosenberger, C., Koesters, R., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031034 · Cited by 87 · see citing works
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Immunohistochemical Detection of Hypoxia-Inducible Factor-1α in Human Renal Allograft Biopsies
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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 · see citing works
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 568 · see citing works
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 · see citing works
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 376 · see citing works
Chronic tissue inflammation and metabolic diseasePreprint
Lee, Y. S., & Olefsky, J. M. (2021) · Genes & Development · doi:10.1101/gad.346312.120 · Cited by 342 · see citing works
“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).”
BackgroundKidney 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 · see citing works
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 · see citing works
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 · see citing works
“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.”
BackgroundSafety 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 · see citing works
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 190 · see citing works
Haase, V. H. (2021) · Kidney International Supplements · doi:10.1016/j.kisu.2020.12.002 · Cited by 203 · see citing works
“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.”
BackgroundHypoxia 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 171 · see citing works
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 156 · see citing works
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 148 · see citing works
“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].”
BackgroundProlyl and lysyl hydroxylases in collagen synthesis
Salo, A. M., & Myllyharju, J. (2020) · Experimental Dermatology · doi:10.1111/exd.14197 · Cited by 134 · see citing works
“[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.”
BackgroundRedox signaling at the crossroads of human health and disease
Zuo, J., Zhang, Z., Luo, M., Zhou, L., Nice, E., Zhang, W., Wang, C., & Huang, C.-H. (2022) · MedComm · doi:10.1002/mco2.127 · Cited by 107 · see citing works
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 · see citing works
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 108 · see citing works
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 113 · see citing works
“…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).”
BackgroundMethodHypoxia, 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 93 · see citing works
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 87 · see citing works
“FIH activity is inhibited at lower oxygen concentrations than PHDs, which thus provides a hierarchic adaptive mechanism to oxygen tension [4].”
BackgroundInfluentialHypoxia 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 86 · see citing works
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 85 · see citing works
“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 80 · see citing works
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 · see citing works
“…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 75 · see citing works
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 76 · see citing works
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 73 · see citing works
“HIF-1α mediates the HIF complex’s oxygen sensitivity and interacts with HIF-1β by an authorized Per–ARNT–Sim (PAS) domain [6].”
BackgroundInfluentialNovel 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 · see citing works
Lim, M., Thompson, J. G., & Dunning, K. R. (2020) · Reproduction · doi:10.1530/rep-20-0509 · Cited by 74 · see citing works
Garone, C., Giorgio, F. D., & Carli, S. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05041-w · Cited by 74 · see citing works
“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].”
BackgroundPseudohypoxic 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 72 · see citing works
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 68 · see citing works
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 · see citing works
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 70 · see citing works
“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 66 · see citing works
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 · see citing works
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 62 · see citing works
Mima, A. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174583 · Cited by 63 · see citing works
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 · see citing works
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 57 · see citing works
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 59 · see citing works
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 53 · see citing works
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 55 · see citing works
“179 Additionally, the heart ‒ kidney axis is underscored in various systemic diseases.”
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 51 · see citing works
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 · see citing works
Li, G., Liu, J., Guan, Y., & Ji, X. (2021) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13754 · Cited by 54 · see citing works
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 45 · see citing works
“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 46 · see citing works
“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 · see citing works
Wang, Y., Liu, X., Huang, W., Liang, J., & Chen, Y. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108303 · Cited by 44 · see citing works
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 · see citing works
Jeelani, I., Moon, J.-S., da Cunha, F. F., Nasamran, C., Jeon, S., Zhang, X.-H., Bandyopadhyay, G. K., Dobaczewska, K., Mikulski, Z., Hosseini, M., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0284 · Cited by 46 · see citing works
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 42 · see citing works
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 42 · see citing works
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 47 · see citing works
“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…”
BackgroundNakanishi, T., & Kuragano, T. (2024) · Clinical Kidney Journal · doi:10.1093/ckj/sfae051 · Cited by 39 · see citing works
“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 ].”
MethodJin, 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 · see citing works
“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].”
BackgroundMethodResultInfluentialWang, 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 · see citing works
Naas, S., Schiffer, M., & Schödel, J. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00201.2023 · Cited by 40 · see citing works
Self-citationHypoxia induces alterations in tRNA modifications involved in translational control
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“the high-altitude hypobaric hypoxic environment [54].”
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“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.”
BackgroundRenal Interstitial Fibroblasts Coproduce Erythropoietin and Renin Under Anaemic Conditions
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“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).”
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“Hypoxia represents a condition under which the body is deprived of adequate oxygen supply at the tissue level [23].”
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“…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).”
BackgroundHypoxia Inducible Factor pathway proteins in high-altitude mammals
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PD-1 immunobiology in glomerulonephritis and renal cell carcinoma
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“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].”
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“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
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Tissue-resident memory T cells in the kidney
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“Given the hypoxic environment in the kidney [47, 48], it is likely that renal TRM cells also upregulate the expression of hypoxia-responsive genes.”
BackgroundFount, fate, features, and function of renal erythropoietin-producing cells
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“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].”
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Human adaptation to hypoxia in critical illness
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Detrimental effects of hypoxia on glomerular podocytes
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“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.”
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“Whereas under normoxia conditions, HIF-1α undergoes hydroxylation and degradation by the proteasome-mediated degradation pathway, hypoxia prevents HIF-1α hydroxylation and degradation [71].”
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“Hif-1 mediates hypoxia and regulates more than 1000 direct transcriptional targets, including metabolic adaptation, angiogenesis, cell cycle and apoptosis (Schodel and Ratcliffe 2019).”
BackgroundInflammatory processes involved in NASH-related hepatocellular carcinoma
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Hypoxic Regulation of the Large-Conductance, Calcium and Voltage-Activated Potassium Channel, BK
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“Furthermore, HIFs are involved in renal inflammation and fibrosis (for review see Schodel and Ratcliffe 2019).”
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“This signal induces its degradation, which is why HIF α cannot bind to HIF β to form the active transcription factor dimer [21].”
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- Authors
- Schödel, J., & Ratcliffe, P. J.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- The Francis Crick Institute (GB)
- Corresponding author
- Ratcliffe, Peter J.
- Venue
- Nature Reviews Nephrology
- Published
- 2019-09-05
- Volume
- 15
- Issue
- 10
- Pages
- 641-659
- ISSN
- 1745-8323 (ISSN-L)
- 1759-5061
- 1759-507X
- 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
- 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
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