title: Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response.
abstract: The generation of reactive oxygen species has a pivotal role in both acute and chronic glomerular injuries in patients with lupus nephritis. As the transcription factor Nrf2 is a major regulator of the antioxidant response and is a primary cellular defense mechanism, we sought to determine a role of Nrf2 in the progression of lupus nephritis. Pathological analyses of renal biopsies from patients with different types of lupus nephritis showed oxidative damage in the glomeruli, accompanied by an active Nrf2 antioxidant response. A murine lupus nephritis model using Nrf2(+/+) and Nrf2(-/-) mice was established using pristine injection. In this model, Nrf2(-/-) mice suffered from greater renal damage and had more severe pathological alterations in the kidney. In addition, Nrf2(+/+) mice showed ameliorative renal function when treated with sulforaphane, an Nrf2 inducer. Nrf2(-/-) mice had higher expression of transforming growth factor β1 (TGFβ1), fibronectin, and iNOS. In primary mouse mesangial cells, the nephritogenic monoclonal antibody R4A activated the nuclear factor-kappa B (NF-κB) pathway and increased the level of reactive oxygen species, iNOS, TGFβ1, and fibronectin. Knockdown of Nrf2 expression aggravated all aforementioned responses induced by R4A. Thus, these results suggest that Nrf2 improves lupus nephritis by neutralizing reactive oxygen species and by negatively regulating the NF-κB and TGFβ1 signaling pathways.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.|Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Medical Microbiology and Parasitology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Tian
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Hongting
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Whitman
authors.affiliation: Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Nong
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004249:DNA Damage; D004195:Disease Models, Animal; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D037741:Fullerenes; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D017879:Isothiocyanates / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008181:Lupus Nephritis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D013454:Sulfoxides; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D005353:Fibronectins; D037741:Fullerenes; D018836:Inflammation Mediators; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D013454:Sulfoxides; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C530172:pristine (C60); D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C016766:sulforaphane
references.citation: Biochem Biophys Res Commun. 2000 Jul 14;273(3):894-8
references.pmid: 10891343
references.citation: Diabetes. 2010 Apr;59(4):850-60
references.pmid: 20103708
references.citation: Physiol Genomics. 2004 Aug 11;18(3):261-72
references.pmid: 15173550
references.citation: J Pharmacol Exp Ther. 2006 Apr;317(1):61-7
references.pmid: 16371450
references.citation: Kidney Int. 2001 Oct;60(4):1343-53
references.pmid: 11576348
references.citation: Lupus. 1998;7(9):604-10
references.pmid: 9884097
references.citation: Mol Cell Biol. 2005 Jul;25(14):5933-46
references.pmid: 15988009
references.citation: Free Radic Res. 1999 Oct;31(4):319-24
references.pmid: 10517536
references.citation: Kidney Int. 2004 May;65(5):1703-13
references.pmid: 15086909
references.citation: Antioxid Redox Signal. 2010 Dec 1;13(11):1623-6
references.pmid: 20486759
references.citation: Trends Mol Med. 2004 Nov;10(11):549-57
references.pmid: 15519281
references.citation: Pulm Pharmacol Ther. 2009 Jun;22(3):221-36
references.pmid: 19138753
references.citation: Lupus. 2010 Jan;19(1):65-72
references.pmid: 19933721
references.citation: Endocr Metab Immune Disord Drug Targets. 2006 Dec;6(4):359-72
references.pmid: 17214582
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:89-116
references.pmid: 16968214
references.citation: Am J Physiol Heart Circ Physiol. 2006 May;290(5):H1862-70
references.pmid: 16339837
references.citation: Life Sci. 2007 Mar 20;80(15):1420-30
references.pmid: 17320913
references.citation: Drug Metab Rev. 2006;38(4):769-89
references.pmid: 17145701
references.citation: J Biol Chem. 2006 Nov 24;281(47):35764-9
references.pmid: 16998237
references.citation: J Exp Med. 1994 Sep 1;180(3):925-32
references.pmid: 8064241
references.citation: Arthritis Rheum. 2006 Jul;54(7):2198-210
references.pmid: 16804897
references.citation: Mini Rev Med Chem. 2003 Sep;3(6):568-75
references.pmid: 12871159
references.citation: Am J Pathol. 2006 Jun;168(6):1960-74
references.pmid: 16723711
references.citation: Life Sci. 2004 Jun 25;75(6):639-53
references.pmid: 15172174
references.citation: Arthritis Rheum. 2010 Jul;62(7):2064-72
references.pmid: 20201076
references.citation: Free Radic Biol Med. 2011 Aug 1;51(3):744-54
references.pmid: 21641991
references.citation: J Am Soc Nephrol. 1999 Feb;10(2):413-24
references.pmid: 10215343
references.citation: Free Radic Res. 2007 Dec;41(12):1301-12
references.pmid: 17957542
references.citation: Antioxid Redox Signal. 2010 Dec 1;13(11):1649-63
references.pmid: 20367496
references.citation: Lupus. 2010 Sep;19(10):1237-42
references.pmid: 20507872
references.citation: Antioxid Redox Signal. 2010 Dec 1;13(11):1679-98
references.pmid: 20486765
references.citation: N Engl J Med. 2010 Sep 9;363(11):1080-2
references.pmid: 20825323
references.citation: J Am Soc Nephrol. 2012 Mar;23(3):381-99
references.pmid: 22282593
references.citation: Kidney Int Suppl. 1994 Feb;45:S111-5
references.pmid: 8158878
references.citation: Arthritis Rheum. 2005 Jan;52(1):192-200
references.pmid: 15641060
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4611-6
references.pmid: 11287661
references.citation: Contrib Nephrol. 2011;169:183-197
references.pmid: 21252519