title: NADPH oxidase-induced NALP3 inflammasome activation is driven by thioredoxin-interacting protein which contributes to podocyte injury in hyperglycemia.
abstract: Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease, and previously we demonstrated that NALP3 inflammasome was involved in the pathogenesis of DN. Here we investigated the mechanisms of NALP3 inflammasome activation in podocyte injury during DN. We found that, besides the activation of NALP3 inflammasome and upregulated thioredoxin-interacting protein (TXNIP), the glomerular expression of gp91 (phox) , a subunit of NADPH oxidase, was enhanced in DN mice simultaneously. Inhibiting NADPH oxidase abrogated NALP3 inflammasome activation, and IL-1β production and eventually protected podocytes from high glucose- (HG-) induced injury. TXNIP, an inhibitor of thioredoxin, acts as a suppressor for antioxidant defense system. Our observation indicated that in HG-exposed podocytes genetic deletion of TXNIP by shRNA reversed gp91 (phox) overexpression and alleviated the injury of podocyte. Collectively, our findings proposed that HG-induced NADPH oxidase activation was driven by TXNIP which subsequently triggered NALP3 inflammasome activation in podocytes and ultimately led to podocyte injury, and blocking TXNIP/NADPH oxidase signaling may be a promising treatment for DN.
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: He
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Chun-Tao
authors.initials: CT
authors.lastname: Lei
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xian-Fang
authors.initials: XF
authors.lastname: Meng
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001706:Biopsy; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D019255:NADPH Oxidases / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D050199:Podocytes / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; C445672:Txnip protein, mouse; D013879:Thioredoxins; D019255:NADPH Oxidases; D020170:Caspase 1
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9035-40
references.pmid: 18577586
references.citation: J Biol Chem. 2005 Nov 25;280(47):39616-26
references.pmid: 16135519
references.citation: J Leukoc Biol. 2004 Sep;76(3):676-84
references.pmid: 15240753
references.citation: Antioxid Redox Signal. 2013 Oct 10;19(11):1266-303
references.pmid: 23244617
references.citation: Kidney Int. 2001 Jun;59(6):2104-13
references.pmid: 11380812
references.citation: Biochim Biophys Acta. 2013 Jun;1833(6):1434-42
references.pmid: 23499875
references.citation: J Am Soc Nephrol. 2010 Oct;21(10):1732-44
references.pmid: 20688930
references.citation: Kidney Int. 2013 Jun;83(6):1029-41
references.pmid: 23325084
references.citation: Nature. 2011 Jan 13;469(7329):221-5
references.pmid: 21124315
references.citation: Biochim Biophys Acta. 2014 Nov;1843(11):2448-60
references.pmid: 25017793
references.citation: J Immunol. 2009 Jul 15;183(2):792-6
references.pmid: 19542372
references.citation: Nature. 2006 Mar 9;440(7081):228-32
references.pmid: 16407890
references.citation: Nat Immunol. 2008 Aug;9(8):866-72
references.pmid: 18604212
references.citation: Kidney Int. 2004 Dec;66(6):2202-13
references.pmid: 15569309
references.citation: Cell Metab. 2012 Aug 8;16(2):265-73
references.pmid: 22883234
references.citation: Arthritis Rheum. 2013 Dec;65(12):3176-85
references.pmid: 24022661
references.citation: Diabetes. 2008 Feb;57(2):460-9
references.pmid: 17959934
references.citation: Nature. 2001 Dec 13;414(6865):813-20
references.pmid: 11742414
references.citation: Nature. 2008 Jun 19;453(7198):1122-6
references.pmid: 18496530
references.citation: Free Radic Biol Med. 2010 Apr 15;48(8):1109-17
references.pmid: 20116427
references.citation: Kidney Int. 2003 Nov;64(5):1632-42
references.pmid: 14531794
references.citation: Nat Immunol. 2010 Feb;11(2):136-40
references.pmid: 20023662
references.citation: Hypertension. 2012 Jul;60(1):154-62
references.pmid: 22647887
references.citation: J Immunol. 2000 Jun 15;164(12):6287-95
references.pmid: 10843682
references.citation: PLoS One. 2013 Oct 28;8(10):e77794
references.pmid: 24204969
references.citation: Annu Rev Genet. 2009;43:335-67
references.pmid: 19691428
references.citation: Diabetes. 2006 Jan;55(1):225-33
references.pmid: 16380497
references.citation: Biochim Biophys Acta. 2010 Apr;1803(4):482-91
references.pmid: 20036696
references.citation: Plant Physiol Biochem. 2010 Dec;48(12):909-30
references.pmid: 20870416
references.citation: Circ Res. 2010 Oct 29;107(9):1058-70
references.pmid: 21030723
references.citation: Vaccine. 2009 May 18;27(23):3013-21
references.pmid: 19428913
references.citation: Mol Immunol. 2008 Apr;45(8):2236-46
references.pmid: 18178252
references.citation: Biochim Biophys Acta. 1994 Sep 13;1219(1):26-32
references.pmid: 8086474
references.citation: Nat Rev Immunol. 2010 Mar;10(3):210-5
references.pmid: 20168318
references.citation: Hypertension. 2009 Jan;53(1):90-6
references.pmid: 19029489
references.citation: Biochem Biophys Res Commun. 2009 Apr 17;381(4):660-5
references.pmid: 19254690
references.citation: Free Radic Biol Med. 2007 Sep 15;43(6):861-8
references.pmid: 17697931
references.citation: J Dermatol. 2006 Oct;33(10):662-9
references.pmid: 17040494
references.citation: Diabetes. 2008 Jun;57(6):1446-54
references.pmid: 18511445
references.citation: N Engl J Med. 2007 Jul 19;357(3):302-3; author reply 303
references.pmid: 17634469
references.citation: Science. 2010 Jan 15;327(5963):296-300
references.pmid: 20075245
references.citation: Am J Physiol Renal Physiol. 2009 Aug;297(2):F410-9
references.pmid: 19474193
references.citation: Clin Rheumatol. 2015 Jul;34(7):1311-6
references.pmid: 24510061
references.citation: J Biol Chem. 2004 Jul 16;279(29):30369-74
references.pmid: 15128745
references.citation: Cell Biol Int. 2011 Aug;35(8):827-34
references.pmid: 21166652
references.citation: J Am Soc Nephrol. 2009 Apr;20(4):730-41
references.pmid: 19211714
references.citation: Kobe J Med Sci. 2007;53(1-2):53-61
references.pmid: 17582205
references.citation: Antioxid Redox Signal. 2013 May 1;18(13):1537-48
references.pmid: 23088210
references.citation: Immunity. 2005 Dec;23(6):587-98
references.pmid: 16356857