{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T22:15:04Z","timestamp":1792275304231,"version":"4.4.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Glomerulonephritis is one of the most serious manifestations of systemic lupus erythematous (SLE). Because SLE is \u226510 times more common in women, a role for estrogens in disease pathogenesis has long been suspected. Estrogen receptor \u03b1 (ER\u03b1) is highly expressed in renal tissue. We asked whether ER\u03b1 expression contributes to the development of immune-mediated nephropathies like in lupus nephritis. We tested the overall effects of estrogen receptors on the immune response by immunization with OVA and induction of chronic graft-versus-host disease in female ER\u03b1-knockout mice. We used nephrotoxic serum nephritis as a model of immune-mediated nephropathy. We investigated the influence of ER\u03b1 on molecular pathways during nephritis by microarray analysis of glomerular extract gene expression. We performed RNA sequencing of lupus patient whole blood to determine common pathways in murine and human nephritis. Absence of ER\u03b1 protects female mice from developing nephritis, despite the presence of immune complexes and the production of proinflammatory cytokines in the kidneys and normal humoral responses to immunization. Time-course microarray analysis of glomeruli during nephrotoxic serum nephritis revealed significant upregulation of genes related to PPAR-mediated lipid metabolism and downregulation of genes in the retinol metabolism in wild-type females compared with ER\u03b1-knockout females. Similarly, RNA sequencing of lupus patient blood revealed similar expression patterns of these same pathways. During nephritis, the altered activity of metabolic pathways, such as retinol metabolism, occurs downstream of ER\u03b1 activation and is essential for the progression to end-stage renal failure.<\/jats:p>","DOI":"10.4049\/jimmunol.1700770","type":"journal-article","created":{"date-parts":[[2017,12,13]],"date-time":"2017-12-13T15:50:21Z","timestamp":1513180221000},"page":"512-522","source":"Crossref","is-referenced-by-count":18,"title":["Estrogen Receptor \u03b1 Signaling Exacerbates Immune-Mediated Nephropathies through Alteration of Metabolic Activity"],"prefix":"10.1093","volume":"200","author":[{"given":"Chelsea","family":"Corradetti","sequence":"first","affiliation":[{"name":"Rheumatology Section, Department of Medicine, Lewis Katz School of Medicine, Temple University , Philadelphia, PA 19140"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelakshi R","family":"Jog","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation , Oklahoma City, OK 73104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Cesaroni","sequence":"additional","affiliation":[{"name":"Janssen Research and Development, LLC , Spring House, PA 19477"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2133-0810","authenticated-orcid":false,"given":"Michael","family":"Madaio","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical College of Georgia, Augusta University , Augusta, GA 30912"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Caricchio","sequence":"additional","affiliation":[{"name":"Rheumatology Section, Department of Medicine, Lewis Katz School of Medicine, Temple University , Philadelphia, PA 19140"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,1,15]]},"reference":[{"key":"2025030610010995800_r1","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/art.38238","article-title":"Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan Lupus Epidemiology and Surveillance Program","volume":"66","author":"Somers","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"2025030610010995800_r2","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1681\/ASN.2006090992","article-title":"Severe lupus nephritis: racial differences in presentation and outcome","volume":"18","author":"Korbet","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025030610010995800_r3","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1097\/BOR.0000000000000089","article-title":"The pathogenesis, diagnosis and treatment of lupus nephritis","volume":"26","author":"Schwartz","year":"2014","journal-title":"Curr. Opin. Rheumatol."},{"key":"2025030610010995800_r4","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/sj.ki.5002328","article-title":"Gender-specific effects of endogenous testosterone: female alpha-estrogen receptor-deficient C57Bl\/6J mice develop glomerulosclerosis","volume":"72","author":"Elliot","year":"2007","journal-title":"Kidney Int."},{"key":"2025030610010995800_r5","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/nrrheum.2014.144","article-title":"Modulation of autoimmune rheumatic diseases by oestrogen and progesterone","volume":"10","author":"Hughes","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"2025030610010995800_r6","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s12016-010-8203-5","article-title":"Estrogen receptors in immunity and autoimmunity","volume":"40","author":"Cunningham","year":"2011","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"2025030610010995800_r7","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/sj.gene.6364458","article-title":"Estrogen receptor-alpha deficiency attenuates autoimmune disease in (NZB \u00d7 NZW)F1 mice","volume":"9","author":"Bynot\u00e9","year":"2008","journal-title":"Genes Immun."},{"key":"2025030610010995800_r8","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1002\/art.34473","article-title":"Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus","volume":"64","author":"Petri","year":"2012","journal-title":"Arthritis Rheum."},{"key":"2025030610010995800_r9","first-page":"288","article-title":"Systemic lupus erythematosus disease activity index 2000","volume":"29","author":"Gladman","year":"2002","journal-title":"J. Rheumatol."},{"key":"2025030610010995800_r10","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1084\/jem.171.2.503","article-title":"Autoantibodies in chronic graft versus host result from cognate T-B interactions","volume":"171","author":"Morris","year":"1990","journal-title":"J. Exp. Med."},{"key":"2025030610010995800_r11","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1084\/jem.20051900","article-title":"Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors","volume":"203","author":"Kaneko","year":"2006","journal-title":"J. Exp. Med."},{"key":"2025030610010995800_r12","doi-asserted-by":"crossref","first-page":"7959","DOI":"10.4049\/jimmunol.179.11.7959","article-title":"Lack of chromatin and nuclear fragmentation in vivo impairs the production of lupus anti-nuclear antibodies","volume":"179","author":"Frisoni","year":"2007","journal-title":"J. Immunol."},{"key":"2025030610010995800_r13","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1111\/j.1749-6632.1997.tb52046.x","article-title":"The roles of B cells in MRL\/lpr murine lupus","volume":"815","author":"Chan","year":"1997","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2025030610010995800_r14","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1038\/ki.1996.175","article-title":"Lupus autoantibodies interact directly with distinct glomerular and vascular cell surface antigens","volume":"49","author":"D\u2019Andrea","year":"1996","journal-title":"Kidney Int."},{"key":"2025030610010995800_r15","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1093\/bioinformatics\/btr490","article-title":"RNA-Seq analysis in MeV","volume":"27","author":"Howe","year":"2011","journal-title":"Bioinformatics"},{"key":"2025030610010995800_r16","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1093\/bioinformatics\/btp120","article-title":"TopHat: discovering splice junctions with RNA-Seq","volume":"25","author":"Trapnell","year":"2009","journal-title":"Bioinformatics"},{"key":"2025030610010995800_r17","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"2025030610010995800_r18","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"2025030610010995800_r19","doi-asserted-by":"crossref","first-page":"11162","DOI":"10.1073\/pnas.90.23.11162","article-title":"Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene","volume":"90","author":"Lubahn","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030610010995800_r20","first-page":"1441","article-title":"Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene","volume":"9","author":"Couse","year":"1995","journal-title":"Mol. Endocrinol."},{"key":"2025030610010995800_r21","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1073\/pnas.88.1.21","article-title":"Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation","volume":"88","author":"Nelson","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030610010995800_r22","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nrneph.2015.33","article-title":"Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis","volume":"11","author":"Mohan","year":"2015","journal-title":"Nat. Rev. Nephrol."},{"key":"2025030610010995800_r23","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.clim.2008.03.508","article-title":"Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse","volume":"128","author":"Svenson","year":"2008","journal-title":"Clin. Immunol."},{"key":"2025030610010995800_r24","doi-asserted-by":"crossref","first-page":"e0163611","DOI":"10.1371\/journal.pone.0163611","article-title":"Immune-mediated nephropathy and systemic autoimmunity in mice does not require receptor interacting protein kinase 3 (RIPK3)","volume":"11","author":"Corradetti","year":"2016","journal-title":"PLoS One"},{"key":"2025030610010995800_r25","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1681\/ASN.2013010026","article-title":"The pathogenesis of lupus nephritis","volume":"24","author":"Lech","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025030610010995800_r26","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1191\/0961203305lu2054oa","article-title":"Pathogenic autoantibodies in lupus nephritis","volume":"14","author":"Waldman","year":"2005","journal-title":"Lupus"},{"key":"2025030610010995800_r27","doi-asserted-by":"crossref","first-page":"7297","DOI":"10.4049\/jimmunol.0803565","article-title":"Poly(ADP-ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation","volume":"182","author":"Jog","year":"2009","journal-title":"J. Immunol."},{"key":"2025030610010995800_r28","doi-asserted-by":"crossref","first-page":"e70926","DOI":"10.1371\/journal.pone.0070926","article-title":"Classical estrogen receptors and ER\u03b1 splice variants in the mouse","volume":"8","author":"Irsik","year":"2013","journal-title":"PLoS One"},{"key":"2025030610010995800_r29","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1084\/jem.121.5.715","article-title":"Experimental glomerulonephritis. Vi. The autologous phase of nephrotoxic serum nephritis","volume":"121","author":"Unanue","year":"1965","journal-title":"J. Exp. Med."},{"key":"2025030610010995800_r30","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"2025030610010995800_r31","doi-asserted-by":"crossref","first-page":"D433","DOI":"10.1093\/nar\/gki005","article-title":"STRING: known and predicted protein-protein associations, integrated and transferred across organisms","volume":"33","author":"von Mering","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2025030610010995800_r32","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1681\/ASN.V12112300","article-title":"Effects of retinoids on the TGF-beta system and extracellular matrix in experimental glomerulonephritis","volume":"12","author":"Morath","year":"2001","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025030610010995800_r33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s00109-008-0404-5","article-title":"Chronic low-dose isotretinoin treatment limits renal damage in subtotally nephrectomized rats","volume":"87","author":"Morath","year":"2009","journal-title":"J. Mol. Med."},{"key":"2025030610010995800_r34","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1046\/j.1523-1755.2001.00056.x","article-title":"Isotretinoin alleviates renal damage in rat chronic glomerulonephritis","volume":"60","author":"Schaier","year":"2001","journal-title":"Kidney Int."},{"key":"2025030610010995800_r35","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1007\/s00109-003-0510-3","article-title":"Retinoic acid receptor alpha and retinoid X receptor specific agonists reduce renal injury in established chronic glomerulonephritis of the rat","volume":"82","author":"Schaier","year":"2004","journal-title":"J. Mol. Med."},{"key":"2025030610010995800_r36","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s10517-007-0413-3","article-title":"Agonists of PPAR-alpha, PPAR-gamma, and RXR inhibit the formation of foam cells from macrophages in mice with inflammation","volume":"144","author":"Dushkin","year":"2007","journal-title":"Bull. Exp. Biol. Med."},{"key":"2025030610010995800_r37","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.bbadis.2004.11.016","article-title":"Gene expression profiling identifies retinoids as potent inducers of macrophage lipid efflux","volume":"1740","author":"Langmann","year":"2005","journal-title":"Biochim. Biophys. Acta"},{"key":"2025030610010995800_r38","doi-asserted-by":"crossref","first-page":"6936","DOI":"10.4049\/jimmunol.171.12.6936","article-title":"Estrogen receptor alpha mediates estrogen\u2019s immune protection in autoimmune disease","volume":"171","author":"Liu","year":"2003","journal-title":"J. Immunol."},{"key":"2025030610010995800_r39","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1016\/j.bbadis.2015.04.019","article-title":"17\u03b2-estradiol enhances the activation of IFN-\u03b1 signaling in B cells by down-regulating the expression of let-7e-5p, miR-98-5p and miR-145a-5p that target IKK\u03b5","volume":"1852","author":"Dong","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"2025030610010995800_r40","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1089\/jir.2011.0073","article-title":"Emerging roles for the interferon-inducible p200-family proteins in sex bias in systemic lupus erythematosus","volume":"31","author":"Choubey","year":"2011","journal-title":"J. Interferon Cytokine Res."},{"key":"2025030610010995800_r41","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/ki.2010.398","article-title":"Testosterone and 17\u03b2-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice","volume":"79","author":"Doublier","year":"2011","journal-title":"Kidney Int."},{"key":"2025030610010995800_r42","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1172\/JCI83005","article-title":"Metabolic regulation of immune responses: therapeutic opportunities","volume":"126","author":"Assmann","year":"2016","journal-title":"J. Clin. Invest."},{"key":"2025030610010995800_r43","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nrneph.2015.215","article-title":"Renal fibrosis in 2015: understanding the mechanisms of kidney fibrosis","volume":"12","author":"Zhou","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"2025030610010995800_r44","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.1046\/j.1523-1755.1999.07113.x","article-title":"Effect of lipoproteins on mesangial cell proliferation","volume":"71","author":"Nishida","year":"1999","journal-title":"Kidney Int. Suppl."},{"key":"2025030610010995800_r45","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/S0140-6736(82)91513-6","article-title":"Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease","volume":"2","author":"Moorhead","year":"1982","journal-title":"Lancet"},{"key":"2025030610010995800_r46","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1159\/000075925","article-title":"Cellular lipid metabolism and the role of lipids in progressive renal disease","volume":"24","author":"Abrass","year":"2004","journal-title":"Am. J. Nephrol."},{"key":"2025030610010995800_r47","first-page":"245","article-title":"Foam cells and the pathogenesis of kidney disease","volume":"24","author":"Eom","year":"2015","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"2025030610010995800_r48","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.immuni.2013.04.005","article-title":"Metabolic pathways in immune cell activation and quiescence","volume":"38","author":"Pearce","year":"2013","journal-title":"Immunity"},{"key":"2025030610010995800_r49","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/j.cell.2009.04.043","article-title":"Genomic antagonism between retinoic acid and estrogen signaling in breast cancer","volume":"137","author":"Hua","year":"2009","journal-title":"Cell"},{"key":"2025030610010995800_r50","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.kint.2016.02.026","article-title":"Disorders of lipid metabolism in nephrotic syndrome: mechanisms and consequences","volume":"90","author":"Vaziri","year":"2016","journal-title":"Kidney Int."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/200\/2\/512\/61497276\/ji1700770.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/200\/2\/512\/61497276\/ji1700770.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T10:12:59Z","timestamp":1741255979000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/200\/2\/512\/7960684"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1]]},"references-count":50,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2018,1,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1700770","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,1]]},"published":{"date-parts":[[2018,1]]}}}