{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T12:27:43Z","timestamp":1784982463270,"version":"3.55.0"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"Postdoctoral Science Foundation of China","doi-asserted-by":"crossref","award":["2021M703608"],"award-info":[{"award-number":["2021M703608"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Tumor necrosis factor alpha-induced protein 9 (TNFAIP9) is a crucial effector molecule that protects cells from inflammatory and metabolic damage. This study focuses on investigating the role and regulatory mechanisms of TNFAIP9 in the progression of chronic kidney disease (CKD). By analyzing CKD-related datasets from the GEO database, we discovered that TNFAIP9 was upregulated in CKD patients and CKD mice compared to their normal controls. To elucidate the functional role of TNFAIP9, we established a mouse model of CKD through a two-step 5\/6 nephrectomy (Nx). The experimental mice were transduced with an adenoviral vector to express TNFAIP9. The results showed that mice undergoing 5\/6-Nx developed evident renal impairment, inflammation, and fibrosis. Overexpression of TNFAIP9 resulted in the remission of renal impairment, a decreased inflammatory response, and a reduced expression of fibrotic markers. In vitro, human renal tubular epithelial human kidney-2 (HK-2) cells were exposed to tumor necrosis factor-alpha (TNF-\u03b1) or transforming growth factor-beta (TGF-\u03b2) to simulate inflammatory and fibrotic conditions, respectively. Then, the overexpression plasmid or small interfering RNA (siRNA) targeting TNFAIP9 was transfected into HK-2 cells to either overexpress or knock down the target protein. Overexpression of TNFAIP9 reduced the TNF-\u03b1-induced inflammatory response, while its knockdown amplified it. Likewise, overexpression of TNFAIP9 decreased the TGF-\u03b2-induced fibrosis, whereas its knockdown heightened it. In summary, it is suggested that TNFAIP9 plays a protective role against the early stage of CKD by suppressing renal inflammation and fibrosis. Therefore, targeting TNFAIP9 could be a promising therapeutic approach for CKD.<\/jats:p>","DOI":"10.1371\/journal.pone.0325334","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T17:50:27Z","timestamp":1749145827000},"page":"e0325334","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["TNFAIP9 protects against the development of the early stage of chronic kidney disease: Focus on inflammation and fibrosis"],"prefix":"10.1371","volume":"20","author":[{"given":"Ying","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqiu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0952-1980","authenticated-orcid":true,"given":"Deyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"pone.0325334.ref001","doi-asserted-by":"crossref","first-page":"17088","DOI":"10.1038\/nrdp.2017.88","article-title":"Chronic kidney disease","volume":"3","author":"P Romagnani","year":"2017","journal-title":"Nat Rev Dis Primers"},{"issue":"10075","key":"pone.0325334.ref002","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/S0140-6736(16)32064-5","article-title":"Chronic kidney disease","volume":"389","author":"AC Webster","year":"2017","journal-title":"Lancet"},{"issue":"9","key":"pone.0325334.ref003","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1369\/0022155419852932","article-title":"Renal inflammation and fibrosis: a double-edged sword","volume":"67","author":"LM Black","year":"2019","journal-title":"J Histochem Cytochem"},{"key":"pone.0325334.ref004","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.bcp.2018.07.039","article-title":"Cardamonin, a natural flavone, alleviates inflammatory bowel disease by the inhibition of NLRP3 inflammasome activation via an AhR\/Nrf2\/NQO1 pathway","volume":"155","author":"K Wang","year":"2018","journal-title":"Biochem Pharmacol"},{"issue":"1","key":"pone.0325334.ref005","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22010408","article-title":"Fibrosis in chronic kidney disease: pathogenesis and consequences","volume":"22","author":"S Panizo","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0325334.ref006","doi-asserted-by":"crossref","DOI":"10.1530\/JOE-16-0594","article-title":"STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper","volume":"234","author":"RT Scarl","year":"2017","journal-title":"J Endocrinol"},{"issue":"45","key":"pone.0325334.ref007","article-title":"Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer","volume":"114","author":"X Xue","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"42","key":"pone.0325334.ref008","doi-asserted-by":"crossref","first-page":"30064","DOI":"10.1074\/jbc.M113.478750","article-title":"Steap4 plays a critical role in osteoclastogenesis in vitro by regulating cellular iron\/reactive oxygen species (ROS) levels and cAMP response element-binding protein (CREB) activation","volume":"288","author":"J Zhou","year":"2013","journal-title":"J Biol Chem"},{"issue":"7","key":"pone.0325334.ref009","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.febslet.2009.03.015","article-title":"Interleukin-1beta is a positive regulator of TIARP\/STAMP2 gene and protein expression in adipocytes in vitro","volume":"583","author":"S Kralisch","year":"2009","journal-title":"FEBS Lett"},{"issue":"7","key":"pone.0325334.ref010","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.3390\/cancers13071579","article-title":"STAMP2 expression mediated by cytokines attenuates their growth-limiting effects in prostate cancer cells","volume":"13","author":"N Pihlstr\u00f8m","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"3","key":"pone.0325334.ref011","first-page":"361","article-title":"STEAP4, a gene associated with insulin sensitivity, is regulated by several adipokines in human adipocytes","volume":"25","author":"X Chen","year":"2010","journal-title":"Int J Mol Med"},{"issue":"6","key":"pone.0325334.ref012","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s00395-020-00826-8","article-title":"The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice","volume":"115","author":"M Batool","year":"2020","journal-title":"Basic Res Cardiol"},{"issue":"2","key":"pone.0325334.ref013","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.jhep.2015.01.025","article-title":"Hepatic STAMP2 alleviates high fat diet-induced hepatic steatosis and insulin resistance","volume":"63","author":"HY Kim","year":"2015","journal-title":"J Hepatol"},{"key":"pone.0325334.ref014","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.2147\/DMSO.S251663","article-title":"STEAP4 inhibits HIF-1\u03b1\/PKM2 signaling and reduces high glucose-induced apoptosis of retinal vascular endothelial cells","volume":"13","author":"L Liu","year":"2020","journal-title":"Diabetes Metab Syndr Obes"},{"key":"pone.0325334.ref015","doi-asserted-by":"crossref","first-page":"108311","DOI":"10.1016\/j.intimp.2021.108311","article-title":"STEAP4 knockdown inhibits the proliferation of prostate cancer cells by activating the cGMP-PKG pathway under lipopolysaccharide-induced inflammatory microenvironment","volume":"101","author":"W Li","year":"2021","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"pone.0325334.ref016","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s12974-021-02146-7","article-title":"STEAP4 expression in CNS resident cells promotes Th17 cell-induced autoimmune encephalomyelitis","volume":"18","author":"J Zhao","year":"2021","journal-title":"J Neuroinflammation"},{"issue":"6","key":"pone.0325334.ref017","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1111\/jcmm.12472","article-title":"Steap4 attenuates high glucose and S100B-induced effects in mesangial cells","volume":"19","author":"CT Chuang","year":"2015","journal-title":"J Cell Mol Med"},{"key":"pone.0325334.ref018","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.bbrc.2021.09.026","article-title":"Overexpressing STAMP2 attenuates diabetic renal injuries via upregulating autophagy in diabetic rats","volume":"579","author":"F-Q Song","year":"2021","journal-title":"Biochem Biophys Res Commun"},{"issue":"5","key":"pone.0325334.ref019","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.kint.2016.01.016","article-title":"The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5\/6 nephrectomy","volume":"89","author":"O Tsuprykov","year":"2016","journal-title":"Kidney Int"},{"issue":"50","key":"pone.0325334.ref020","doi-asserted-by":"crossref","first-page":"19290","DOI":"10.1074\/jbc.RA118.005457","article-title":"The signaling protein Wnt5a promotes TGF\u03b21-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap\/Taz","volume":"293","author":"Y Feng","year":"2018","journal-title":"J Biol Chem"},{"issue":"11","key":"pone.0325334.ref021","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1681\/ASN.2018111162","article-title":"Integrin-linked kinase deficiency in collecting duct principal cell promotes necroptosis of principal cell and contributes to kidney inflammation and fibrosis","volume":"30","author":"M Huang","year":"2019","journal-title":"J Am Soc Nephrol"},{"key":"pone.0325334.ref022","doi-asserted-by":"crossref","first-page":"119109","DOI":"10.1016\/j.lfs.2021.119109","article-title":"High salt aggravates renal inflammation via promoting pro-inflammatory macrophage in 5\/6-nephrectomized rat","volume":"274","author":"Y Liu","year":"2021","journal-title":"Life Sci"},{"key":"pone.0325334.ref023","article-title":"Phenotypic characterization of macrophages from rat kidney by flow cytometry","volume":"116","author":"A Rubio-Navarro","year":"2016","journal-title":"JoVE"},{"issue":"3","key":"pone.0325334.ref024","article-title":"6-Shogaol protects against ischemic acute kidney injury by modulating NF-\u03baB and heme oxygenase-1 pathways","volume":"317","author":"SJ Han","year":"2019","journal-title":"Am J Physiol Renal Physiol"},{"issue":"11","key":"pone.0325334.ref025","doi-asserted-by":"crossref","first-page":"594","DOI":"10.5483\/BMBRep.2020.53.11.153","article-title":"Lin28a attenuates TGF-\u03b2-induced renal fibrosis","volume":"53","author":"G-S Jung","year":"2020","journal-title":"BMB Rep"},{"issue":"4","key":"pone.0325334.ref026","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1182\/blood-2006-02-003681","article-title":"The Steap proteins are metalloreductases","volume":"108","author":"RS Ohgami","year":"2006","journal-title":"Blood"},{"issue":"36","key":"pone.0325334.ref027","doi-asserted-by":"crossref","first-page":"33938","DOI":"10.1074\/jbc.M105726200","article-title":"Tumor necrosis factor-alpha-induced adipose-related protein (TIARP), a cell-surface protein that is highly induced by tumor necrosis factor-alpha and adipose conversion","volume":"276","author":"M Moldes","year":"2001","journal-title":"J Biol Chem"},{"key":"pone.0325334.ref028","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0014-5793(04)00096-1","article-title":"Interleukin-6 is a positive regulator of tumor necrosis factor alpha-induced adipose-related protein in 3T3-L1 adipocytes","volume":"560","author":"M Fasshauer","year":"2004","journal-title":"FEBS Lett"},{"issue":"1","key":"pone.0325334.ref029","doi-asserted-by":"crossref","first-page":"128","DOI":"10.3109\/s10165-011-0475-y","article-title":"Six-transmembrane epithelial antigen of prostate4 (STEAP4) is a tumor necrosis factor alpha-induced protein that regulates IL-6, IL-8, and cell proliferation in synovium from patients with rheumatoid arthritis","volume":"22","author":"Y Tanaka","year":"2012","journal-title":"Mod Rheumatol"},{"issue":"10","key":"pone.0325334.ref030","doi-asserted-by":"crossref","first-page":"622","DOI":"10.3858\/emm.2012.44.10.071","article-title":"Hepatic STAMP2 decreases hepatitis B virus X protein-associated metabolic deregulation","volume":"44","author":"HY Kim","year":"2012","journal-title":"Exp Mol Med"},{"issue":"1","key":"pone.0325334.ref031","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1038\/s41467-020-14698-y","article-title":"Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis","volume":"11","author":"Y Liao","year":"2020","journal-title":"Nat Commun"},{"key":"pone.0325334.ref032","doi-asserted-by":"crossref","first-page":"701721","DOI":"10.3389\/fimmu.2021.701721","article-title":"Stamp2 protects from maladaptive structural remodeling and systolic dysfunction in post-ischemic hearts by attenuating neutrophil activation","volume":"12","author":"M Mollenhauer","year":"2021","journal-title":"Front Immunol"},{"issue":"2","key":"pone.0325334.ref033","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.semnephrol.2020.01.011","article-title":"Pathophysiology of AKI to CKD progression","volume":"40","author":"Y Sato","year":"2020","journal-title":"Semin Nephrol"},{"issue":"4","key":"pone.0325334.ref034","doi-asserted-by":"crossref","DOI":"10.3390\/toxins12040227","article-title":"Inflammation and premature ageing in chronic kidney disease","volume":"12","author":"T Ebert","year":"2020","journal-title":"Toxins"},{"issue":"3","key":"pone.0325334.ref035","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1097\/00041552-200105000-00007","article-title":"Macrophages in renal inflammation","volume":"10","author":"LP Erwig","year":"2001","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"pone.0325334.ref036","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1146\/annurev-physiol-022516-034219","article-title":"Macrophages in renal injury and repair","volume":"79","author":"SC Huen","year":"2017","journal-title":"Annu Rev Physiol"},{"key":"pone.0325334.ref037","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.ebiom.2016.10.008","article-title":"Inhibition of G0\/G1 switch 2 ameliorates renal inflammation in chronic kidney disease","volume":"13","author":"N Matsunaga","year":"2016","journal-title":"EBioMedicine"},{"key":"pone.0325334.ref038","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1146\/annurev-physiol-022516-034227","article-title":"Mechanisms of renal fibrosis","volume":"80","author":"BD Humphreys","year":"2018","journal-title":"Annu Rev Physiol"},{"issue":"9","key":"pone.0325334.ref039","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1369\/0022155419849388","article-title":"Extracellular matrix in kidney fibrosis: more than just a scaffold","volume":"67","author":"RD B\u00fclow","year":"2019","journal-title":"J Histochem Cytochem"},{"issue":"7","key":"pone.0325334.ref040","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1016\/j.ekir.2021.04.023","article-title":"Chronic inflammation in chronic kidney disease progression: role of Nrf2","volume":"6","author":"P Stenvinkel","year":"2021","journal-title":"Kidney Int Rep"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0325334","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T17:50:35Z","timestamp":1749145835000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0325334"}},"subtitle":[],"editor":[{"given":"Doa'a G. F.","family":"Al-u'datt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,6,5]]},"references-count":40,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0325334","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,5]]}}}