{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T23:35:39Z","timestamp":1791934539808,"version":"4.3.4"},"reference-count":28,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,12,18]],"date-time":"2019-12-18T00:00:00Z","timestamp":1576627200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81670655"],"award-info":[{"award-number":["81670655"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81700584"],"award-info":[{"award-number":["81700584"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hypoxia\u2010induced extracellular matrix (ECM) deposition is an important cause of renal fibrosis that is triggered by unknown mechanisms. Human epididymis secretory protein 4 (HE4) is a newly discovered key molecule that causes ECM deposition. We used the unilateral ureteral obstruction (UUO) mouse model to investigate the expression and mechanisms of HE4 in the pathogenesis of renal fibrosis. Results were confirmed in the HK2 cell line and in human donors of kidney tissue with chronic kidney disease. Hypoxia significantly increased HE4 in renal tubular epithelial cells. HE4 overexpression activated the NF\u2010\u03baB pathway through the NF\u2010\u03baB transcription\u2010activating group P65 by phosphorylation and nuclear translocation. NF\u2010\u03baB upregulated tissue inhibitor metalloproteinases 1, which may inhibit ECM degradation through inhibition of matrix metallopeptidase 2 activity. Silencing HE4 inhibited hypoxia\u2010induced ECM deposition and alleviated fibrosis in UUO mice in vivo and blocked NF\u2010\u03baB activation in vitro. Expression of HE4 in the tubulointerstitium was positively correlated with tubulointerstitial fibrosis in tissue samples from patients with chronic kidney disease. Our results suggest that hypoxia induces renal fibrosis by upregulating HE4 and activating the HIF\u20101\u03b1\/HE4\/NF\u2010\u03baB signaling pathway. Uncovering the molecular mechanisms and function of HE4 overexpression in hypoxia\u2010induced renal fibrosis will provide important insights into understanding renal fibrosis and antifibrotic strategies.<\/jats:p>","DOI":"10.1096\/fj.201901950r","type":"journal-article","created":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T02:21:53Z","timestamp":1576722113000},"page":"2554-2567","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Hypoxia\u2010induced HE4 in tubular epithelial cells promotes extracellular matrix accumulation and renal fibrosis via NF\u2010\u03baB"],"prefix":"10.1096","volume":"34","author":[{"given":"Lei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Nephrology Xijing Hospital Fourth Military Medical University Xi'an China"},{"name":"Department of Nephrology The 987 Hospital of PLA Joint Logistics Support Force Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology Xijing Hospital Fourth Military Medical University Xi'an China"},{"name":"School of Medicine, Xi'an PeiHua University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Nephrology Xijing Hospital Fourth Military Medical University Xi'an China"},{"name":"State Key Laboratory of Cancer Biology Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minna","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology Xijing Hospital Fourth Military Medical University Xi'an China"},{"name":"State Key Laboratory of Cancer Biology Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Nephrology Xijing Hospital Fourth Military Medical University Xi'an China"},{"name":"State Key Laboratory of Cancer Biology Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nephrology Xijing Hospital Fourth Military Medical University Xi'an China"},{"name":"State Key Laboratory of Cancer Biology Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Medicine Mayo Clinic College of Medicine and Mayo Graduate School Rochester MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Ning","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology Fourth Military Medical University Xi'an China"},{"name":"Department of Geriatrics Xijing Hospital Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiren","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Nephrology Xijing Hospital Fourth Military Medical University Xi'an China"},{"name":"State Key Laboratory of Cancer Biology Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.350"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00123"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2144"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41232-017-0048-3"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-012-9398-z"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00419.x"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-011-9266-y"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.4048\/jbc.2011.14.2.88"},{"issue":"5","key":"e_1_2_9_10_1","first-page":"1138","article-title":"Regulation of colon carcinoma cell invasion by hypoxia\u2010inducible factor 1","volume":"63","author":"Krishnamachary B","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209273"},{"issue":"7","key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/ki.2008.349","article-title":"Matrix metalloproteinases and matrix receptors in progression and reversal of kidney disease: therapeutic perspectives","volume":"74","author":"Ronco P","year":"2008","journal-title":"Kidney Int"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-06-2066"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4402132"},{"issue":"12","key":"e_1_2_9_15_1","first-page":"3810","article-title":"Hypoxia promotes fibrogenesis in vivo via HIF\u20101 stimulation of epithelial\u2010to\u2010mesenchymal transition","volume":"117","author":"Higgins DF","year":"2007","journal-title":"J Clin Invest"},{"issue":"9","key":"e_1_2_9_16_1","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.4161\/cc.7.9.5804","article-title":"Hypoxia\u2010inducible factor signaling in the development of tissue fibrosis","volume":"7","author":"Higgins DF","year":"2008","journal-title":"Cell Cycle"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod45.2.350"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2010.157073"},{"issue":"3","key":"e_1_2_9_19_1","first-page":"661","article-title":"Human epididymis protein 4: a novel serum inflammatory biomarker in cystic","volume":"150","author":"Nagy B","year":"2016","journal-title":"Fibrosis"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11682"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.21954"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2989"},{"issue":"2","key":"e_1_2_9_23_1","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1097\/01.ASN.0000111247.76908.59","article-title":"beta(2)\u2010Adrenoceptor activation attenuates endotoxin\u2010induced acute renal failure","volume":"15","author":"Nakamura A","year":"2004","journal-title":"J Am Soc Nephrol"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2009.62"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(86)90346-6"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00795-016-0146-3"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules181013061"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3109\/10799893.2015.1061002"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-012-0983-z"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1096%2Ffj.201901950R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201901950R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.201901950R","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201901950R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:56:48Z","timestamp":1761674208000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.201901950R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,18]]},"references-count":28,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,2]]}},"alternative-id":["10.1096\/fj.201901950R"],"URL":"https:\/\/doi.org\/10.1096\/fj.201901950r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,18]]},"assertion":[{"value":"2019-08-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}