{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T05:43:43Z","timestamp":1777700623685,"version":"3.51.4"},"reference-count":79,"publisher":"IMR Press","issue":"4","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors have recently been approved for clinical use in the treatment of renal anemia. HIF-PH inhibitors were developed following studies investigating the role of HIFs and their molecular mechanisms. Unlike erythropoiesis-stimulating agents, these orally administered agents improve renal anemia in patients with chronic kidney disease (CKD) and chronic inflammation. HIF-PH inhibitors improve renal anemia by stabilizing HIF-2\u03b1, which increases erythropoietin production. They also improve iron metabolism by suppressing hepcidin and inducing the expression of iron transport-related genes. The renoprotective effects of HIF-PH inhibitors are controversial, owing to the opposing effects of hypoxia-inducible factor 1-alpha (HIF-1\u03b1) and hypoxia-inducible factor 2-alpha (HIF-2\u03b1) on kidney injury. They induce the expression of both HIF-1\u03b1 and HIF-2\u03b1. HIF-2\u03b1 plays a key role in erythropoietin production and mitigates CKD. Although HIF-1\u03b1 contributes to cell survival under hypoxic conditions, its overexpression is suspected to exacerbate kidney injury in CKD. This review summarizes the development of HIF and HIF-PH, from their discovery to the elucidation of their regulatory mechanisms and the development of HIF-PH inhibitors. We reviewed basic research and recently published clinical studies investigating the effects of HIF-PH inhibitors on renal injury, focusing on their clinical use in treating renal injury rather than renal anemia. We discuss the possible benefits of HIF-PH inhibitors used clinically for acute and chronic kidney injury, especially in the advanced stages of CKD.<\/jats:p>","DOI":"10.31083\/fbl47718","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T09:29:27Z","timestamp":1777454967000},"source":"Crossref","is-referenced-by-count":0,"title":["Potential Application of HIF-PH Inhibitors to Treat Kidney Diseases"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0827-9619","authenticated-orcid":true,"given":"Yuichiro","family":"Izumi","sequence":"first","affiliation":[{"name":"Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 860-8556 Kumamoto, Kumamoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9380-1653","authenticated-orcid":true,"given":"Yukiko","family":"Yasuoka","sequence":"additional","affiliation":[{"name":"Department of Physiology, Kitasato University School of Medicine, 252-0374 Sagamihara, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayoshi","family":"Nanami","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Renal Medicine, Hyogo Medical University, 663-8501 Nishinomiya, Hyogo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4816-0321","authenticated-orcid":true,"given":"Katsumasa","family":"Kawahara","sequence":"additional","affiliation":[{"name":"Department of Physiology, Kitasato University School of Medicine, 252-0374 Sagamihara, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7831-7380","authenticated-orcid":true,"given":"Hiroshi","family":"Nonoguchi","sequence":"additional","affiliation":[{"name":"Nephrology, Internal Medicine, Sagamihara Red-Cross Hospital, 252-0157 Sagamihara, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Shi Y, Gilkes DM. HIF-1 and HIF-2 in cancer: structure, regulation, and therapeutic prospects. Cellular and Molecular Life Sciences: CMLS. 2025; 82: 44.","DOI":"10.1007\/s00018-024-05537-0"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Wiesener MS, J\u00fcrgensen JS, Rosenberger C, Scholze CK, H\u00f6rstrup JH, Warnecke C, et al. Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. FASEB Journal. 2003; 17: 271\u2013273.","DOI":"10.1096\/fj.02-0445fje"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Heidbreder M, Fr\u00f6hlich F, J\u00f6hren O, Dendorfer A, Qadri F, Dominiak P. Hypoxia rapidly activates HIF-3alpha mRNA expression. FASEB Journal. 2003; 17: 1541\u20131543.","DOI":"10.1096\/fj.02-0963fje"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Tanaka T, Wiesener M, Bernhardt W, Eckardt KU, Warnecke C. The human HIF (hypoxia-inducible factor)-3alpha gene is a HIF-1 target gene and may modulate hypoxic gene induction. The Biochemical Journal. 2009; 424: 143\u2013151.","DOI":"10.1042\/BJ20090120"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Heikkil\u00e4 M, Pasanen A, Kivirikko KI, Myllyharju J. Roles of the human hypoxia-inducible factor (HIF)-3\u03b1 variants in the hypoxia response. Cellular and Molecular Life Sciences: CMLS. 2011; 68: 3885\u20133901.","DOI":"10.1007\/s00018-011-0679-5"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Kleibert M, Tkacz K, Winiarska K, Ma\u0142yszko J, Cudnoch-J\u0119drzejewska A. The role of hypoxia-inducible factors 1 and 2 in the pathogenesis of diabetic kidney disease. Journal of Nephrology. 2025; 38: 37\u201347.","DOI":"10.1007\/s40620-024-02152-x"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Buchholz B, Eckardt KU. Role of oxygen and the HIF-pathway in polycystic kidney disease. Cellular Signalling. 2020; 69: 109524.","DOI":"10.1016\/j.cellsig.2020.109524"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. Hypoxia-inducible nuclear factors bind to an enhancer element located 3\u2019 to the human erythropoietin gene. Proceedings of the National Academy of Sciences of the United States of America. 1991; 88: 5680\u20135684.","DOI":"10.1073\/pnas.88.13.5680"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Semenza GL, Wang GL. 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. Molecular and Cellular Biology. 1992; 12: 5447\u20135454.","DOI":"10.1128\/mcb.12.12.5447-5454.1992"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. The Journal of Biological Chemistry. 1995; 270: 1230\u20131237.","DOI":"10.1074\/jbc.270.3.1230"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes & Development. 1997; 11: 72\u201382.","DOI":"10.1101\/gad.11.1.72"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC. Acute postnatal ablation of Hif-2alpha results in anemia. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104: 2301\u20132306.","DOI":"10.1073\/pnas.0608382104"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett MJ, Bennett M, et al. HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood. 2005; 105: 3133\u20133140.","DOI":"10.1182\/blood-2004-05-1695"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proceedings of the National Academy of Sciences of the United States of America. 1996; 93: 10595\u201310599.","DOI":"10.1073\/pnas.93.20.10595"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Salceda S, Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. The Journal of Biological Chemistry. 1997; 272: 22642\u201322647.","DOI":"10.1074\/jbc.272.36.22642"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999; 399: 271\u2013275.","DOI":"10.1038\/20459"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nature Cell Biology. 2000; 2: 423\u2013427.","DOI":"10.1038\/35017054"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001; 292: 464\u2013468.","DOI":"10.1126\/science.1059817"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Min JH, Yang H, Ivan M, Gertler F, Kaelin WG Jr, Pavletich NP. Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling. Science. 2002; 296: 1886\u20131889.","DOI":"10.1126\/science.1073440"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Hon WC, Wilson MI, Harlos K, Claridge TDW, Schofield CJ, Pugh CW, et al. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature. 2002; 417: 975\u2013978.","DOI":"10.1038\/nature00767"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"An award to oxygen sensing. Nature Biomedical Engineering. 2019; 3: 843\u2013844.","DOI":"10.1038\/s41551-019-0479-z"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Hurst JH. William Kaelin, Peter Ratcliffe, and Gregg Semenza receive the 2016 Albert Lasker Basic Medical Research Award. The Journal of Clinical Investigation. 2016; 126: 3628\u20133638.","DOI":"10.1172\/JCI90055"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Besarab A, Provenzano R, Hertel J, Zabaneh R, Klaus SJ, Lee T, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrology, Dialysis, Transplantation. 2015; 30: 1665\u20131673.","DOI":"10.1093\/ndt\/gfv302"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich K, et al. Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients. Journal of the American Society of Nephrology: JASN. 2016; 27: 1225\u20131233.","DOI":"10.1681\/ASN.2015030241"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Dhillon S. Roxadustat: First global approval. Drugs. 2019; 79: 563\u2013572.","DOI":"10.1007\/s40265-019-01077-1"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Akizawa T, Tsubakihara Y, Nangaku M, Endo Y, Nakajima H, Kohno T, et al. Effects of Daprodustat, a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Anemia Management in Japanese Hemodialysis Subjects. American Journal of Nephrology. 2017; 45: 127\u2013135.","DOI":"10.1159\/000454818"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH. Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney International. 2016; 90: 1115\u20131122.","DOI":"10.1016\/j.kint.2016.07.019"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Akizawa T, Nangaku M, Yamaguchi T, Arai M, Koretomo R, Maeda K, et al. Enarodustat, Conversion and Maintenance Therapy for Anemia in Hemodialysis Patients: A Randomized, Placebo-Controlled Phase 2b Trial Followed by Long-Term Trial. Nephron. 2019; 143: 77\u201385.","DOI":"10.1159\/000500487"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Macdougall IC, Akizawa T, Berns JS, Bernhardt T, Krueger T. Effects of Molidustat in the Treatment of Anemia in CKD. Clinical Journal of the American Society of Nephrology: CJASN. 2019; 14: 28\u201339.","DOI":"10.2215\/CJN.02510218"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Padhi D, Ni L, Cooke B, Marino R, Jang G. An extended terminal half-life for darbepoetin alfa: results from a single-dose pharmacokinetic study in patients with chronic kidney disease not receiving dialysis. Clinical Pharmacokinetics. 2006; 45: 503\u2013510.","DOI":"10.2165\/00003088-200645050-00005"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Locatelli F, Reigner B. C.E.R.A.: pharmacodynamics, pharmacokinetics and efficacy in patients with chronic kidney disease. Expert Opinion on Investigational Drugs. 2007; 16: 1649\u20131661.","DOI":"10.1517\/13543784.16.10.1649"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Locatelli F, Del Vecchio L, Elliott S. The anaemia treatment journey of CKD patients: from epoetins to hypoxia-inducible factor-prolyl hydroxylase inhibitors. Clinical Kidney Journal. 2023; 16: 1563\u20131579.","DOI":"10.1093\/ckj\/sfad105"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Ito M, Tanaka T, Ishii T, Wakashima T, Fukui K, Nangaku M. Prolyl hydroxylase inhibition protects the kidneys from ischemia via upregulation of glycogen storage. Kidney International. 2020; 97: 687\u2013701.","DOI":"10.1016\/j.kint.2019.10.020"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Yang H, Wu Y, Cheng M, Zhang M, Qiu X, Liu S, et al. Roxadustat (FG-4592) protects against ischaemia-induced acute kidney injury via improving CD73 and decreasing AIM2 inflammasome activation. Nephrology, Dialysis, Transplantation. 2023; 38: 858\u2013875.","DOI":"10.1093\/ndt\/gfac308"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Yasuoka Y, Izumi Y, Fukuyama T, Oshima T, Yamazaki T, Uematsu T, et al. Tubular Endogenous Erythropoietin Protects Renal Function against Ischemic Reperfusion Injury. International Journal of Molecular Sciences. 2024; 25: 1223.","DOI":"10.3390\/ijms25021223"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Rajendran G, Schonfeld MP, Tiwari R, Huang S, Torosyan R, Fields T, et al. Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1. Journal of the American Society of Nephrology: JASN. 2020; 31: 501\u2013516.","DOI":"10.1681\/ASN.2019050523"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Kapitsinou PP, Sano H, Michael M, Kobayashi H, Davidoff O, Bian A, et al. Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. The Journal of Clinical Investigation. 2014; 124: 2396\u20132409.","DOI":"10.1172\/JCI69073"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Kapitsinou PP, Jaffe J, Michael M, Swan CE, Duffy KJ, Erickson-Miller CL, et al. Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury. American Journal of Physiology. Renal Physiology. 2012; 302: F1172\u2013F1179.","DOI":"10.1152\/ajprenal.00667.2011"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Deguchi H, Ikeda M, Ide T, Tadokoro T, Ikeda S, Okabe K, et al. Roxadustat Markedly Reduces Myocardial Ischemia Reperfusion Injury in Mice. Circulation Journal. 2020; 84: 1028\u20131033.","DOI":"10.1253\/circj.CJ-19-1039"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Steenhard BM, Freeburg PB, Isom K, Stroganova L, Borza DB, Hudson BG, et al. Kidney development and gene expression in the HIF2alpha knockout mouse. Developmental Dynamics. 2007; 236: 1115\u20131125.","DOI":"10.1002\/dvdy.21106"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Yasuoka Y, Izumi Y, Nagai T, Fukuyama T, Nakayama Y, Inoue H, et al. Fludrocortisone stimulates erythropoietin production in the intercalated cells of the collecting ducts. Biochemical and Biophysical Research Communications. 2018; 503: 3121\u20133127.","DOI":"10.1016\/j.bbrc.2018.08.102"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. The Journal of Clinical Investigation. 2007; 117: 3810\u20133820.","DOI":"10.1172\/JCI30487"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Kobayashi H, Gilbert V, Liu Q, Kapitsinou PP, Unger TL, Rha J, et al. Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury. Journal of Immunology. 2012; 188: 5106\u20135115.","DOI":"10.4049\/jimmunol.1103377"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Kong KH, Oh HJ, Lim BJ, Kim M, Han KH, Choi YH, et al. Selective tubular activation of hypoxia-inducible factor-2\u03b1 has dual effects on renal fibrosis. Scientific Reports. 2017; 7: 11351.","DOI":"10.1038\/s41598-017-11829-2"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Schley G, Klanke B, Kalucka J, Schatz V, Daniel C, Mayer M, et al. Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis. Kidney International. 2019; 96: 378\u2013396.","DOI":"10.1016\/j.kint.2019.02.016"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"Zhao Y, Zeng H, Liu B, He X, Chen JX. Endothelial prolyl hydroxylase 2 is necessary for angiotensin II-mediated renal fibrosis and injury. American Journal of Physiology. Renal Physiology. 2020; 319: F345\u2013F357.","DOI":"10.1152\/ajprenal.00032.2020"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"Yu X, Fang Y, Liu H, Zhu J, Zou J, Xu X, et al. The balance of beneficial and deleterious effects of hypoxia-inducible factor activation by prolyl hydroxylase inhibitor in rat remnant kidney depends on the timing of administration. Nephrology, Dialysis, Transplantation. 2012; 27: 3110\u20133119.","DOI":"10.1093\/ndt\/gfr754"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Kim DA, Lee MR, Oh HJ, Kim M, Kong KH. Effects of long-term tubular HIF-2\u03b1 overexpression on progressive renal fibrosis in a chronic kidney disease model. BMB Reports. 2023; 56: 196\u2013201.","DOI":"10.5483\/BMBRep.2022-0145"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Yasuoka Y, Izumi Y, Fukuyama T, Omiya H, Pham TD, Inoue H, et al. Effects of Roxadustat on Erythropoietin Production in the Rat Body. Molecules. 2022; 27: 1119.","DOI":"10.3390\/molecules27031119"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"Wang S, Zeng H, Chen ST, Zhou L, Xie XJ, He X, et al. Ablation of endothelial prolyl hydroxylase domain protein-2 promotes renal vascular remodelling and fibrosis in mice. Journal of Cellular and Molecular Medicine. 2017; 21: 1967\u20131978.","DOI":"10.1111\/jcmm.13117"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"Yu X, Fang Y, Ding X, Liu H, Zhu J, Zou J, et al. Transient hypoxia-inducible factor activation in rat renal ablation and reduced fibrosis with L-mimosine. Nephrology. 2012; 17: 58\u201367.","DOI":"10.1111\/j.1440-1797.2011.01498.x"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"Fang Y, Yu X, Liu Y, Kriegel AJ, Heng Y, Xu X, et al. miR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by HIF-\u03b1 activation. American Journal of Physiology. Renal Physiology. 2013; 304: F1274\u2013F1282.","DOI":"10.1152\/ajprenal.00287.2012"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Nordquist L, Friederich-Persson M, Fasching A, Liss P, Shoji K, Nangaku M, et al. Activation of hypoxia-inducible factors prevents diabetic nephropathy. Journal of the American Society of Nephrology: JASN. 2015; 26: 328\u2013338.","DOI":"10.1681\/ASN.2013090990"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Jiang N, Zhao H, Han Y, Li L, Xiong S, Zeng L, et al. HIF-1\u03b1 ameliorates tubular injury in diabetic nephropathy via HO-1-mediated control of mitochondrial dynamics. Cell Proliferation. 2020; 53: e12909.","DOI":"10.1111\/cpr.12909"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"Bohuslavova R, Cerychova R, Nepomucka K, Pavlinkova G. Renal injury is accelerated by global hypoxia-inducible factor 1 alpha deficiency in a mouse model of STZ-induced diabetes. BMC Endocrine Disorders. 2017; 17: 48.","DOI":"10.1186\/s12902-017-0200-8"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"Jiao Y, Jiang H, Lu H, Yang Y, Zhang Y, Zhang K, et al. Deficiency of hypoxia inducible factor-1\u03b1 promoted progression of diabetic nephropathy with hypertension. Experimental and Therapeutic Medicine. 2018; 16: 3658\u20133662.","DOI":"10.3892\/etm.2018.6621"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"Nayak BK, Shanmugasundaram K, Friedrichs WE, Cavaglierii RC, Patel M, Barnes J, et al. HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice. Diabetes. 2016; 65: 1387\u20131397.","DOI":"10.2337\/db15-0519"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"Sugahara M, Tanaka S, Tanaka T, Saito H, Ishimoto Y, Wakashima T, et al. Prolyl Hydroxylase Domain Inhibitor Protects against Metabolic Disorders and Associated Kidney Disease in Obese Type 2 Diabetic Mice. Journal of the American Society of Nephrology: JASN. 2020; 31: 560\u2013577.","DOI":"10.1681\/ASN.2019060582"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"Sung PH, Yue Y, Chen YL, Chiang JY, Cheng BC, Yang CC, et al. Combined dapagliflozin and roxadustat effectively protected heart and kidney against cardiorenal syndrome-induced damage in rodent through activation of cell stress-Nfr2\/ARE signalings and stabilizing HIF-1\u03b1. Biomedicine & Pharmacotherapy. 2024; 180: 117567.","DOI":"10.1016\/j.biopha.2024.117567"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Bessho R, Takiyama Y, Takiyama T, Kitsunai H, Takeda Y, Sakagami H, et al. Hypoxia-inducible factor-1\u03b1 is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy. Scientific Reports. 2019; 9: 14754.","DOI":"10.1038\/s41598-019-51343-1"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"Ume AC, Wenegieme TY, Adams DN, Adesina SE, Williams CR. Zinc Deficiency: A Potential Hidden Driver of the Detrimental Cycle of Chronic Kidney Disease and Hypertension. Kidney360. 2023; 4: 398\u2013404.","DOI":"10.34067\/KID.0007812021"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"Zhang X, Liang D, Fan J, Lian X, Zhao Y, Wang X, et al. Zinc Attenuates Tubulointerstitial Fibrosis in Diabetic Nephropathy Via Inhibition of HIF Through PI-3K Signaling. Biological Trace Element Research. 2016; 173: 372\u2013383.","DOI":"10.1007\/s12011-016-0661-z"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"Shimokawa H, Satoh K. 2015 ATVB Plenary Lecture: translational research on rho-kinase in cardiovascular medicine. Arteriosclerosis, Thrombosis, and Vascular Biology. 2015; 35: 1756\u20131769.","DOI":"10.1161\/ATVBAHA.115.305353"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"Matoba K, Kawanami D, Okada R, Tsukamoto M, Kinoshita J, Ito T, et al. Rho-kinase inhibition prevents the progression of diabetic nephropathy by downregulating hypoxia-inducible factor 1\u03b1. Kidney International. 2013; 84: 545\u2013554.","DOI":"10.1038\/ki.2013.130"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"Li QY, Liu F, Tang X, Fu H, Mao J. Renoprotective Role of Hypoxia-Inducible Factors and the Mechanism. Kidney Diseases. 2021; 8: 44\u201356.","DOI":"10.1159\/000520141"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"Chertow GM, Pergola PE, Farag YMK, Agarwal R, Arnold S, Bako G, et al. Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD. The New England Journal of Medicine. 2021; 384: 1589\u20131600.","DOI":"10.1056\/NEJMoa2035938"},{"key":"ref67","doi-asserted-by":"publisher","unstructured":"Singh AK, Carroll K, McMurray JJV, Solomon S, Jha V, Johansen KL, et al. Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis. The New England Journal of Medicine. 2021; 385: 2313\u20132324.","DOI":"10.1056\/NEJMoa2113380"},{"key":"ref68","doi-asserted-by":"publisher","unstructured":"Barratt J, Dellanna F, Portoles J, Choukroun G, De Nicola L, Young J, et al. Safety of Roxadustat Versus Erythropoiesis-Stimulating Agents in Patients with Anemia of Non-dialysis-Dependent or Incident-to-Dialysis Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies. Advances in Therapy. 2023; 40: 1546\u20131559.","DOI":"10.1007\/s12325-023-02433-0"},{"key":"ref69","doi-asserted-by":"publisher","unstructured":"Yamamoto H, Nobori K, Matsuda Y, Hayashi Y, Hayasaki T, Akizawa T. Molidustat for Renal Anemia in Nondialysis Patients Previously Treated with Erythropoiesis-Stimulating Agents: A Randomized, Open-Label, Phase 3 Study. American Journal of Nephrology. 2021; 52: 884\u2013893.","DOI":"10.1159\/000518072"},{"key":"ref70","doi-asserted-by":"publisher","unstructured":"Yamamoto H, Nobori K, Matsuda Y, Hayashi Y, Hayasaki T, Akizawa T. Efficacy and Safety of Molidustat for Anemia in ESA-Naive Nondialysis Patients: A Randomized, Phase 3 Trial. American Journal of Nephrology. 2021; 52: 871\u2013883.","DOI":"10.1159\/000518071"},{"key":"ref71","doi-asserted-by":"publisher","unstructured":"Ha JT, Hiremath S, Jun M, Green SC, Wheeler DC, Coyne DW, et al. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in Kidney Disease. NEJM Evidence. 2024; 3: EVIDoa2300189.","DOI":"10.1056\/EVIDoa2300189"},{"key":"ref72","doi-asserted-by":"publisher","unstructured":"Ren S, Yao X, Li Y, Zhang Y, Tong C, Feng Y. Efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitor treatment for anemia in chronic kidney disease: an umbrella review of meta-analyses. Frontiers in Pharmacology. 2023; 14: 1296702.","DOI":"10.3389\/fphar.2023.1296702"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"Stoumpos S, Crowe K, Sarafidis P, Barratt J, Bolignano D, Del Vecchio L, et al. Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in chronic kidney disease: a clinical practice document by the European Renal Best Practice board of the European Renal Association. Nephrology, Dialysis, Transplantation. 2024; 39: 1710\u20131730.","DOI":"10.1093\/ndt\/gfae075"},{"key":"ref74","doi-asserted-by":"publisher","unstructured":"Liu F, Wang J, Ye Q, Fu H, Mao J. Roxadustat for Renal Anemia in ESRD from PKD Patients: Is It Safe Enough? Journal of the American Society of Nephrology: JASN. 2021; 32: 1005.","DOI":"10.1681\/ASN.2020111664"},{"key":"ref75","doi-asserted-by":"publisher","unstructured":"Yap DYH, McMahon LP, Hao CM, Hu N, Okada H, Suzuki Y, et al. Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF-PH inhibitors. Nephrology. 2021; 26: 105\u2013118.","DOI":"10.1111\/nep.13835"},{"key":"ref76","doi-asserted-by":"publisher","unstructured":"Shimada Y, Izumi Y, Yasuoka Y, Oshima T, Nagaba Y, Nanami M, et al. Renoprotective Effects of Daprodustat in Patients with Chronic Kidney Disease and Renal Anemia. International Journal of Molecular Sciences. 2024; 25: 9468.","DOI":"10.3390\/ijms25179468"},{"key":"ref77","doi-asserted-by":"publisher","unstructured":"Hida Y, Imamura T, Kinugawa K. Clinical Implication of HIF-PH Inhibitor in Patients with Heart Failure, Chronic Kidney Disease, and Renal Anemia. Journal of Clinical Medicine. 2024; 13: 7619.","DOI":"10.3390\/jcm13247619"},{"key":"ref78","doi-asserted-by":"publisher","unstructured":"Ravenna L, Salvatori L, Russo MA. HIF3\u03b1: the little we know. The FEBS Journal. 2016; 283: 993\u20131003.","DOI":"10.1111\/febs.13572"},{"key":"ref79","doi-asserted-by":"publisher","unstructured":"Duan C. Hypoxia-inducible factor 3 biology: complexities and emerging themes. American Journal of Physiology. Cell Physiology. 2016; 310: C260\u2013C269.","DOI":"10.1152\/ajpcell.00315.2015"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/4\/10.31083\/FBL47718","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T09:30:58Z","timestamp":1777455058000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/4\/10.31083\/FBL47718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,21]]},"references-count":79,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026]]}},"alternative-id":["S2768-6701(25)01974-4"],"URL":"https:\/\/doi.org\/10.31083\/fbl47718","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,21]]},"article-number":"47718"}}