{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:52:01Z","timestamp":1792687921303,"version":"4.5.0"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sig Transduct Target Ther"],"DOI":"10.1038\/s41392-026-02653-0","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:04:19Z","timestamp":1776729859000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypoxia inducible factor network reflects kidney disease progression in diabetes and sodium-glucose co-transporters inhibition"],"prefix":"10.1038","volume":"11","author":[{"given":"Viji","family":"Nair","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Minakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1518-9320","authenticated-orcid":false,"given":"Cathy","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine C.","family":"Berthier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hartman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajasree","family":"Menon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian","family":"Fermin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar A.","family":"Otto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9087-4585","authenticated-orcid":false,"given":"Debora L.","family":"Gisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3066-2876","authenticated-orcid":false,"given":"Michael T.","family":"Eadon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2804-127X","authenticated-orcid":false,"given":"Sanjay","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye Ji","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Pyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Eichinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadhl M.","family":"Alakwaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8661-5134","authenticated-orcid":false,"given":"Michael P.","family":"Rose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalita","family":"Subramanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3779-4583","authenticated-orcid":false,"given":"Jamal","family":"El Saghir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Beamish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey B.","family":"Hodgin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4244-8335","authenticated-orcid":false,"given":"Frank C.","family":"Brosius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petter","family":"Bjornstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7927-608X","authenticated-orcid":false,"given":"Jennifer L.","family":"Harder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Werner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Kretzler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Schaub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"2653_CR1","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.2215\/CJN.02980322","volume":"17","author":"KR Tuttle","year":"2022","unstructured":"Tuttle, K. R. et al. Moving from evidence to implementation of breakthrough therapies for diabetic kidney disease. Clin. J. Am. Soc. Nephrol. 17, 1092\u20131103 (2022).","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"2653_CR2","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1016\/j.kint.2020.02.041","volume":"98","author":"AC Hesp","year":"2020","unstructured":"Hesp, A. C. et al. The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors? Kidney Int. 98, 579\u2013589 (2020).","journal-title":"Kidney Int."},{"key":"2653_CR3","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1038\/s41581-019-0182-z","volume":"15","author":"J Sch\u00f6del","year":"2019","unstructured":"Sch\u00f6del, J. & Ratcliffe, P. J. Mechanisms of hypoxia signalling: new implications for nephrology. Nat. Rev. Nephrol. 15, 641\u2013659 (2019).","journal-title":"Nat. Rev. Nephrol."},{"key":"2653_CR4","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1111\/j.1749-6632.2009.05030.x","volume":"1177","author":"VH Haase","year":"2009","unstructured":"Haase, V. H. Pathophysiological consequences of HIF activation: HIF as a modulator of fibrosis. Ann. N. Y Acad. Sci. 1177, 57\u201365 (2009).","journal-title":"Ann. N. Y Acad. Sci."},{"key":"2653_CR5","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/sj.ki.5002567","volume":"73","author":"C Rosenberger","year":"2008","unstructured":"Rosenberger, C. et al. Adaptation to hypoxia in the diabetic rat kidney. Kidney Int. 73, 34\u201342 (2008).","journal-title":"Kidney Int."},{"key":"2653_CR6","first-page":"S74","volume":"65","author":"LG Fine","year":"1998","unstructured":"Fine, L. G., Orphanides, C. & Norman, J. T. Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int. Suppl. 65, S74\u2013S78 (1998).","journal-title":"Kidney Int. Suppl."},{"key":"2653_CR7","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1038\/ki.2008.350","volume":"74","author":"LG Fine","year":"2008","unstructured":"Fine, L. G. & Norman, J. T. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int. 74, 867\u2013872 (2008).","journal-title":"Kidney Int."},{"key":"2653_CR8","doi-asserted-by":"publisher","first-page":"F1269","DOI":"10.1152\/ajprenal.00543.2015","volume":"310","author":"AT Layton","year":"2016","unstructured":"Layton, A. T., Vallon, V. & Edwards, A. Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. Am. J. Physiol. Ren. Physiol. 310, F1269\u2013F1283 (2016).","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"2653_CR9","doi-asserted-by":"publisher","first-page":"F807","DOI":"10.1152\/ajprenal.00049.2016","volume":"310","author":"S Franz\u00e9n","year":"2016","unstructured":"Franz\u00e9n, S., Pihl, L., Khan, N., Gustafsson, H. & Palm, F. Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice. Am. J. Physiol. Ren. Physiol. 310, F807\u2013F809 (2016).","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"2653_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08492-y","volume":"7","author":"N Shved","year":"2017","unstructured":"Shved, N. et al. Transcriptome-based network analysis reveals renal cell type-specific dysregulation of hypoxia-associated transcripts. Sci. Rep. 7, 8576 (2017).","journal-title":"Sci. Rep."},{"key":"2653_CR11","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1016\/j.kint.2017.10.020","volume":"93","author":"M Pruijm","year":"2018","unstructured":"Pruijm, M. et al. Reduced cortical oxygenation predicts a progressive decline of renal function in patients with chronic kidney disease. Kidney Int. 93, 932\u2013940 (2018).","journal-title":"Kidney Int."},{"key":"2653_CR12","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abn4965","volume":"8","author":"J Hansen","year":"2022","unstructured":"Hansen, J. et al. A reference tissue atlas for the human kidney. Sci. Adv. 8, eabn4965 (2022).","journal-title":"Sci. Adv."},{"key":"2653_CR13","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1681\/ASN.2005070757","volume":"17","author":"M Nangaku","year":"2006","unstructured":"Nangaku, M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J. Am. Soc. Nephrol. 17, 17\u201325 (2006).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2653_CR14","doi-asserted-by":"publisher","first-page":"48403","DOI":"10.1074\/jbc.M209114200","volume":"277","author":"EL Page","year":"2002","unstructured":"Page, E. L., Robitaille, G. A., Pouyssegur, J. & Richard, D. E. Induction of hypoxia-inducible factor-1alpha by transcriptional and translational mechanisms. J. Biol. Chem. 277, 48403\u201348409 (2002).","journal-title":"J. Biol. Chem."},{"key":"2653_CR15","doi-asserted-by":"publisher","first-page":"C439","DOI":"10.1152\/ajpcell.00294.2002","volume":"284","author":"J Zhou","year":"2003","unstructured":"Zhou, J., Fandrey, J., Schumann, J., Tiegs, G. & Brune, B. NO and TNF-alpha released from activated macrophages stabilize HIF-1alpha in resting tubular LLC-PK1 cells. Am. J. Physiol. Cell Physiol. 284, C439\u2013C446 (2003).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"2653_CR16","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1097\/01.ASN.0000017223.49823.2A","volume":"13","author":"C Rosenberger","year":"2002","unstructured":"Rosenberger, C. et al. Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. J. Am. Soc. Nephrol. 13, 1721\u20131732 (2002).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2653_CR17","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1681\/ASN.2006090998","volume":"19","author":"P Hill","year":"2008","unstructured":"Hill, P. et al. Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 19, 39\u201346 (2008).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2653_CR18","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1681\/ASN.2007040419","volume":"19","author":"A Weidemann","year":"2008","unstructured":"Weidemann, A. et al. HIF activation protects from acute kidney injury. J. Am. Soc. Nephrol. 19, 486\u2013494 (2008).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2653_CR19","doi-asserted-by":"publisher","first-page":"1970","DOI":"10.1681\/ASN.2005121302","volume":"17","author":"WM Bernhardt","year":"2006","unstructured":"Bernhardt, W. M. et al. Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J. Am. Soc. Nephrol. 17, 1970\u20131978 (2006).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2653_CR20","doi-asserted-by":"publisher","first-page":"F1023","DOI":"10.1152\/ajprenal.90209.2008","volume":"295","author":"K Kimura","year":"2008","unstructured":"Kimura, K. et al. Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am. J. Physiol. Ren. Physiol. 295, F1023\u2013F1029 (2008).","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"2653_CR21","doi-asserted-by":"publisher","first-page":"1979","DOI":"10.1016\/S0002-9440(10)63249-X","volume":"165","author":"T Tanaka","year":"2004","unstructured":"Tanaka, T., Miyata, T., Inagi, R., Fujita, T. & Nangaku, M. Hypoxia in renal disease with proteinuria and\/or glomerular hypertension. Am. J. Pathol. 165, 1979\u20131992 (2004).","journal-title":"Am. J. Pathol."},{"key":"2653_CR22","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1097\/MNH.0b013e3283328eed","volume":"19","author":"T Tanaka","year":"2010","unstructured":"Tanaka, T. & Nangaku, M. The role of hypoxia, increased oxygen consumption, and hypoxia-inducible factor-1 alpha in progression of chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 19, 43\u201350 (2010).","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"2653_CR23","first-page":"3810","volume":"117","author":"DF Higgins","year":"2007","unstructured":"Higgins, D. F. et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest. 117, 3810\u20133820 (2007).","journal-title":"J. Clin. Invest."},{"key":"2653_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15972-8","volume":"7","author":"J Hu","year":"2017","unstructured":"Hu, J. et al. Hypoxia inducible factor-1alpha mediates the profibrotic effect of albumin in renal tubular cells. Sci. Rep. 7, 15878 (2017).","journal-title":"Sci. Rep."},{"key":"2653_CR25","doi-asserted-by":"publisher","first-page":"594","DOI":"10.2353\/ajpath.2010.090268","volume":"176","author":"MA Neusser","year":"2010","unstructured":"Neusser, M. A. et al. Human nephrosclerosis triggers a hypoxia-related glomerulopathy. Am. J. Pathol. 176, 594\u2013607 (2010).","journal-title":"Am. J. Pathol."},{"key":"2653_CR26","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1056\/NEJMoa2024816","volume":"383","author":"HJL Heerspink","year":"2020","unstructured":"Heerspink, H. J. L. et al. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 383, 1436\u20131446 (2020).","journal-title":"N. Engl. J. Med."},{"key":"2653_CR27","doi-asserted-by":"publisher","first-page":"2295","DOI":"10.1056\/NEJMoa1811744","volume":"380","author":"V Perkovic","year":"2019","unstructured":"Perkovic, V. et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl. J. Med. 380, 2295\u20132306 (2019).","journal-title":"N. Engl. J. Med."},{"key":"2653_CR28","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1056\/NEJMoa1515920","volume":"375","author":"C Wanner","year":"2016","unstructured":"Wanner, C. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375, 323\u2013334 (2016).","journal-title":"N. Engl. J. Med."},{"key":"2653_CR29","doi-asserted-by":"publisher","first-page":"F1343","DOI":"10.1152\/ajprenal.00007.2015","volume":"308","author":"AT Layton","year":"2015","unstructured":"Layton, A. T., Vallon, V. & Edwards, A. Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. Am. J. Physiol. Ren. Physiol. 308, F1343\u2013F1357 (2015).","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"2653_CR30","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1056\/NEJMoa1901713","volume":"381","author":"N Chen","year":"2019","unstructured":"Chen, N. et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N. Engl. J. Med. 381, 1011\u20131022 (2019).","journal-title":"N. Engl. J. Med."},{"key":"2653_CR31","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1056\/NEJMoa1813599","volume":"381","author":"N Chen","year":"2019","unstructured":"Chen, N. et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N. Engl. J. Med. 381, 1001\u20131010 (2019).","journal-title":"N. Engl. J. Med."},{"key":"2653_CR32","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.kint.2023.05.009","volume":"104","author":"E Ku","year":"2023","unstructured":"Ku, E. et al. Novel anemia therapies in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 104, 655\u2013680 (2023).","journal-title":"Kidney Int."},{"key":"2653_CR33","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1016\/j.kint.2019.12.007","volume":"97","author":"S Hasegawa","year":"2020","unstructured":"Hasegawa, S. et al. The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney disease. Kidney Int. 97, 934\u2013950 (2020).","journal-title":"Kidney Int."},{"key":"2653_CR34","doi-asserted-by":"publisher","first-page":"e207","DOI":"10.1182\/blood-2010-10-314427","volume":"117","author":"J Sch\u00f6del","year":"2011","unstructured":"Sch\u00f6del, J. et al. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood 117, e207\u2013e217 (2011).","journal-title":"Blood"},{"key":"2653_CR35","doi-asserted-by":"publisher","first-page":"40296","DOI":"10.1074\/jbc.M302560200","volume":"278","author":"MO Leonard","year":"2003","unstructured":"Leonard, M. O., Cottell, D. C., Godson, C., Brady, H. R. & Taylor, C. T. The role of HIF-1 alpha in transcriptional regulation of the proximal tubular epithelial cell response to hypoxia. J. Biol. Chem. 278, 40296\u201340304 (2003).","journal-title":"J. Biol. Chem."},{"key":"2653_CR36","doi-asserted-by":"publisher","first-page":"15215","DOI":"10.1074\/jbc.M511408200","volume":"281","author":"GP Elvidge","year":"2006","unstructured":"Elvidge, G. P. et al. Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways. J. Biol. Chem. 281, 15215\u201315226 (2006).","journal-title":"J. Biol. Chem."},{"key":"2653_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18638-8","volume":"11","author":"J Xin","year":"2020","unstructured":"Xin, J. et al. Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation. Nat. Commun. 11, 4928 (2020).","journal-title":"Nat. Commun."},{"key":"2653_CR38","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","volume":"1","author":"A Liberzon","year":"2015","unstructured":"Liberzon, A. et al. The Molecular Signatures Database (MSigDB) Hallmark Gene Set Collection. Cell Syst. 1, 417\u2013425 (2015).","journal-title":"Cell Syst."},{"key":"2653_CR39","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1016\/S0047-6374(03)00166-0","volume":"124","author":"H Kim","year":"2003","unstructured":"Kim, H. et al. Analysis of the effect of aging on the response to hypoxia by cDNA microarray. Mech. Ageing Dev. 124, 941\u2013949 (2003).","journal-title":"Mech. Ageing Dev."},{"key":"2653_CR40","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1182\/blood-2004-07-2958","volume":"105","author":"DJ Manalo","year":"2005","unstructured":"Manalo, D. J. et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105, 659\u2013669 (2005).","journal-title":"Blood"},{"key":"2653_CR41","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/s41586-023-05769-3","volume":"619","author":"BB Lake","year":"2023","unstructured":"Lake, B. B. et al. An atlas of healthy and injured cell states and niches in the human kidney. Nature 619, 585\u2013594 (2023).","journal-title":"Nature"},{"key":"2653_CR42","doi-asserted-by":"publisher","first-page":"2993","DOI":"10.2337\/db06-0477","volume":"55","author":"H Schmid","year":"2006","unstructured":"Schmid, H. et al. Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy. Diabetes 55, 2993\u20133003 (2006).","journal-title":"Diabetes"},{"key":"2653_CR43","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s10157-006-0421-z","volume":"10","author":"Y Yasuda","year":"2006","unstructured":"Yasuda, Y., Cohen, C. D., Henger, A. & Kretzler, M. Gene expression profiling analysis in nephrology: towards molecular definition of renal disease. Clin. Exp. Nephrol. 10, 91\u201398 (2006).","journal-title":"Clin. Exp. Nephrol."},{"key":"2653_CR44","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/S0168-9525(02)02591-X","volume":"18","author":"S Fessele","year":"2002","unstructured":"Fessele, S., Maier, H., Zischek, C., Nelson, P. J. & Werner, T. Regulatory context is a crucial part of gene function. Trends Genet. 18, 60\u201363 (2002).","journal-title":"Trends Genet."},{"key":"2653_CR45","doi-asserted-by":"publisher","unstructured":"Minakawa, A. et al. Dapagliflozin mitigates hypoxia-induced metabolic stress, kidney tubular cell death and fibrosis. bioRxiv https:\/\/doi.org\/10.64898\/2025.12.13.693777 (2025)","DOI":"10.64898\/2025.12.13.693777"},{"key":"2653_CR46","doi-asserted-by":"publisher","first-page":"F1217","DOI":"10.1152\/ajprenal.00294.2016","volume":"311","author":"AT Layton","year":"2016","unstructured":"Layton, A. T., Laghmani, K., Vallon, V. & Edwards, A. Solute transport and oxygen consumption along the nephrons: effects of Na+ transport inhibitors. Am. J. Physiol. Ren. Physiol. 311, F1217\u2013f1229 (2016).","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"2653_CR47","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1159\/000449323","volume":"44","author":"N Kushida","year":"2016","unstructured":"Kushida, N. et al. Hypoxia-Inducible Factor-1\u03b1 Activates the Transforming Growth Factor-\u03b2\/SMAD3 Pathway in Kidney Tubular Epithelial Cells. Am. J. Nephrol. 44, 276\u2013285 (2016).","journal-title":"Am. J. Nephrol."},{"key":"2653_CR48","doi-asserted-by":"publisher","first-page":"13505","DOI":"10.1073\/pnas.0906670106","volume":"106","author":"H Thangarajah","year":"2009","unstructured":"Thangarajah, H. et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc. Natl. Acad. Sci. USA 106, 13505\u201313510 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2653_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-23060-9","volume":"12","author":"Y Zhang","year":"2022","unstructured":"Zhang, Y., Wang, S., Hu, H. & Li, X. A systematic study of HIF1A cofactors in hypoxic cancer cells. Sci. Rep. 12, 18962 (2022).","journal-title":"Sci. Rep."},{"key":"2653_CR50","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/188671a0","volume":"188","author":"K Aukland","year":"1960","unstructured":"Aukland, K. & Krog, J. Renal oxygen tension. Nature 188, 671 (1960).","journal-title":"Nature"},{"key":"2653_CR51","doi-asserted-by":"publisher","first-page":"7004","DOI":"10.1128\/MCB.22.20.7004-7014.2002","volume":"22","author":"CC Hudson","year":"2002","unstructured":"Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol. Cell Biol. 22, 7004\u20137014 (2002).","journal-title":"Mol. Cell Biol."},{"key":"2653_CR52","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1681\/ASN.2015030302","volume":"27","author":"YH You","year":"2016","unstructured":"You, Y. H., Quach, T., Saito, R., Pham, J. & Sharma, K. Metabolomics reveals a key role for fumarate in mediating the effects of NADPH oxidase 4 in diabetic kidney disease. J. Am. Soc. Nephrol. 27, 466\u2013481 (2016).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2653_CR53","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.ccr.2004.11.022","volume":"7","author":"MA Selak","year":"2005","unstructured":"Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7, 77\u201385 (2005).","journal-title":"Cancer Cell"},{"key":"2653_CR54","doi-asserted-by":"crossref","unstructured":"Schaub, J. A. et al. SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes. J. Clin. Invest. 133, e164486 (2023).","DOI":"10.1172\/JCI164486"},{"key":"2653_CR55","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.86976","volume":"1","author":"KM Sas","year":"2016","unstructured":"Sas, K. M. et al. Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications. JCI Insight 1, e86976 (2016).","journal-title":"JCI Insight"},{"key":"2653_CR56","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/nature11245","volume":"489","author":"MB Gerstein","year":"2012","unstructured":"Gerstein, M. B. et al. Architecture of the human regulatory network derived from ENCODE data. Nature 489, 91\u2013100 (2012).","journal-title":"Nature"},{"key":"2653_CR57","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.2337\/db12-1416","volume":"62","author":"S Martini","year":"2013","unstructured":"Martini, S. et al. From single nucleotide polymorphism to transcriptional mechanism: a model for FRMD3 in diabetic nephropathy. Diabetes 62, 2605\u20132612 (2013).","journal-title":"Diabetes"},{"key":"2653_CR58","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01995-2","volume":"9","author":"J Rozman","year":"2018","unstructured":"Rozman, J. et al. Identification of genetic elements in metabolism by high-throughput mouse phenotyping. Nat. Commun. 9, 288 (2018).","journal-title":"Nat. Commun."},{"key":"2653_CR59","doi-asserted-by":"publisher","first-page":"5682","DOI":"10.1073\/pnas.0511257103","volume":"103","author":"CD Cohen","year":"2006","unstructured":"Cohen, C. D. et al. Comparative promoter analysis allows de novo identification of specialized cell junction-associated proteins. Proc. Natl. Acad. Sci. USA 103, 5682\u20135687 (2006).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2653_CR60","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1128\/MCB.01051-12","volume":"33","author":"MF Stein","year":"2013","unstructured":"Stein, M. F. et al. Multiple interferon regulatory factor and NF-\u03baB sites cooperate in mediating cell-type- and maturation-specific activation of the human CD83 promoter in dendritic cells. Mol. Cell Biol. 33, 1331\u20131344 (2013).","journal-title":"Mol. Cell Biol."},{"key":"2653_CR61","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1096\/fj.02-0955rev","volume":"17","author":"T Werner","year":"2003","unstructured":"Werner, T., Fessele, S., Maier, H. & Nelson, P. J. Computer modeling of promoter organization as a tool to study transcriptional coregulation. Faseb J. 17, 1228\u20131237 (2003).","journal-title":"Faseb J."},{"key":"2653_CR62","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44467-6","volume":"15","author":"DL Gisch","year":"2024","unstructured":"Gisch, D. L. et al. The chromatin landscape of healthy and injured cell types in the human kidney. Nat. Commun. 15, 433 (2024).","journal-title":"Nat. Commun."},{"key":"2653_CR63","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1046\/j.1523-1755.2002.00113.x","volume":"61","author":"CD Cohen","year":"2002","unstructured":"Cohen, C. D., Frach, K., Schl\u00f6ndorff, D. & Kretzler, M. Quantitative gene expression analysis in renal biopsies: a novel protocol for a high-throughput multicenter application. Kidney Int. 61, 133\u2013140 (2002).","journal-title":"Kidney Int."},{"key":"2653_CR64","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.2337\/db19-0204","volume":"68","author":"Y Fan","year":"2019","unstructured":"Fan, Y. et al. Comparison of kidney transcriptomic profiles of early and advanced diabetic nephropathy reveals potential new mechanisms for disease progression. Diabetes 68, 2301\u20132314 (2019).","journal-title":"Diabetes"},{"key":"2653_CR65","doi-asserted-by":"publisher","first-page":"e186070","DOI":"10.1172\/jci.insight.186070","volume":"10","author":"F Alakwaa","year":"2025","unstructured":"Alakwaa, F. et al. Leveraging complementary multi-omics data integration methods for mechanistic insights in kidney diseases. JCI Insight 10, e186070 (2025).","journal-title":"JCI Insight"},{"key":"2653_CR66","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1136\/annrheumdis-2017-212935","volume":"77","author":"PC Grayson","year":"2018","unstructured":"Grayson, P. C. et al. Metabolic pathways and immunometabolism in rare kidney diseases. Ann. Rheum. Dis. 77, 1226\u20131233 (2018).","journal-title":"Ann. Rheum. Dis."},{"key":"2653_CR67","doi-asserted-by":"publisher","first-page":"797","DOI":"10.2337\/db20-er04b","volume":"69","author":"Y Fan","year":"2020","unstructured":"Fan, Y. et al. Erratum. Comparison of kidney transcriptomic profiles of early and advanced diabetic nephropathy reveals potential new mechanisms for disease progression. Diabetes 2019;68:2301-2314. Diabetes 69, 797 (2020).","journal-title":"Diabetes"}],"container-title":["Signal Transduction and Targeted Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02653-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02653-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02653-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:04:21Z","timestamp":1776729861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02653-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,21]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2653"],"URL":"https:\/\/doi.org\/10.1038\/s41392-026-02653-0","relation":{},"ISSN":["2059-3635"],"issn-type":[{"value":"2059-3635","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,21]]},"assertion":[{"value":"16 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 February 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"P.B. reports serving or having served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli-Lilly, LG Chemistry, Sanofi, Novo Nordisk, and Horizon Pharma. P.B. also serves or has served on the advisory boards and\/or steering committees of AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, Lilly, and XORTX. P.B. serves as DMC Chair for Bayer and a DMC member for Cytel. P.B. reports grant funding from AstraZeneca, Novo Nordisk, Eli Lilly, Boehringer-Ingelheim, Merck, and Amgen\/Horizon Pharma. M.K. reports grants and contracts through the University of Michigan outside of this work from Chan Zuckerberg Initiative, AstraZeneca, NovoNordisk, Eli Lilly, Boehringer-Ingelheim, European Union Innovative Medicine Initiative, Certa Therapeutics, RenalytixAI, Regeneron, Novo Nordisk, Sanofi, Dimerix, Travere and Vera Therapeutics. M.K. has received consulting fees through the University of Michigan from NovoNordisk, Alexion, Novartis, Roche Diagnostics and Vera Therapeutics. In addition, M.K. and V.N. have a patent, PCT\/EP2014\/073413 \u201cBiomarkers and methods for progression prediction for chronic kidney disease\u201d licensed. All other authors do not have conflicts to report.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"144"}}