title: Matrix metalloproteinase 12 modulates high-fat-diet induced glomerular fibrogenesis and inflammation in a mouse model of obesity.
abstract: Obesity-induced kidney injury contributes to albuminuria, which is characterized by a progressive decline in renal function leading to glomerulosclerosis and renal fibrosis. Matrix metalloproteinases (MMPs) modulate inflammation and fibrosis by degrading a variety of extracellular matrix and regulating the activities of effector proteins. Abnormal regulation of MMP-12 expression has been implicated in abdominal aortic aneurysm, atherosclerosis, and emphysema, but the underlying mechanisms remain unclear. The present study examined the function of MMP-12 in glomerular fibrogenesis and inflammation using apo E(-/-) or apo E(-/-)MMP-12(-/-) mice and maintained on a high-fat-diet (HFD) for 3, 6, or 9 months. MMP-12 deletion reduced glomerular matrix accumulation, and downregulated the expression of NADPH oxidase 4 and the subunit-p67(phox), indicating the inhibition of renal oxidative stress. In addition, the expression of the inflammation-associated molecule MCP-1 and macrophage marker-CD11b was decreased in glomeruli of apo E(-/-)MMP-12(-/-) mice fed HFD. MMP-12 produced by macrophages infiltrating into glomeruli contributed to the degradation of collagen type IV and fibronectin. Crescent formation due to renal oxidative stress in Bowman's space was a major factor in the development of fibrogenesis and inflammation. These results suggest that regulating MMP-12 activity could be a therapeutic strategy for the treatment of crescentic glomerulonephritis and fibrogenesis.
authors.affiliation: Department of Nephrology, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.|Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050071, China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Niu
authors.affiliation: Department of Nephrology, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.|Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050071, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Nephrology, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.|Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050071, China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Chi
authors.affiliation: Department of Nephrology, First Central Hospital of Baoding, Baoding, 071000, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Zhuang
authors.affiliation: Department of Nephrology, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.|Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050071, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.|Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050071, China.
authors.forename: Maodong
authors.initials: M
authors.lastname: Liu
authors.affiliation: Key Laboratory of Medical Biotechnology of Hebei Province and Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, China.|Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050017, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Nie
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D005355:Fibrosis; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007678:Kidney Glomerulus / Q000201:enzymology* / Q000473:pathology; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D004041:Dietary Fats; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse
references.citation: Exp Biol Med (Maywood). 2008 Jan;233(1):4-11
references.pmid: 18156300
references.citation: Free Radic Biol Med. 2012 Aug 15;53(4):842-53
references.pmid: 22749956
references.citation: Am J Pathol. 2006 Jul;169(1):32-46
references.pmid: 16816359
references.citation: Apoptosis. 2012 Dec;17(12):1261-74
references.pmid: 23054083
references.citation: Am J Pathol. 2001 Oct;159(4):1313-21
references.pmid: 11583959
references.citation: Kidney Int. 2006 Jan;69(2):213-7
references.pmid: 16408108
references.citation: J Clin Invest. 2010 Feb;120(2):422-32
references.pmid: 20101093
references.citation: J Am Soc Nephrol. 2011 Oct;22(10):1846-55
references.pmid: 21921143
references.citation: Kidney Int. 2000 Oct;58(4):1588-602
references.pmid: 11012893
references.citation: J Immunol. 2003 Mar 15;170(6):3377-85
references.pmid: 12626598
references.citation: Kidney Int. 2008 Jan;73(1):19-33
references.pmid: 17928825
references.citation: World J Nephrol. 2013 Aug 6;2(3):84-9
references.pmid: 24255890
references.citation: Cell Metab. 2012 Feb 8;15(2):201-8
references.pmid: 22326221
references.citation: Am J Respir Cell Mol Biol. 2007 Aug;37(2):210-21
references.pmid: 17446527
references.citation: Endocrinology. 2006 Jan;147(1):44-50
references.pmid: 16210374
references.citation: J Biol Chem. 1992 Mar 5;267(7):4664-71
references.pmid: 1537850
references.citation: Am J Pathol. 2004 Oct;165(4):1375-83
references.pmid: 15466401
references.citation: Am J Physiol Renal Physiol. 2009 Jan;296(1):F118-26
references.pmid: 18971213
references.citation: Am J Physiol Renal Physiol. 2007 Mar;292(3):F905-11
references.pmid: 17190907
references.citation: J Immunol. 2010 Apr 1;184(7):3955-63
references.pmid: 20181883
references.citation: Am J Physiol Renal Physiol. 2010 Dec;299(6):F1348-58
references.pmid: 20630933
references.citation: Nephrology (Carlton). 2012 May;17(4):322-9
references.pmid: 22257277
references.citation: J Cell Sci. 2013 Sep 1;126(Pt 17):3948-60
references.pmid: 23813962
references.citation: Am J Physiol Renal Physiol. 2013 Nov 1;305(9):F1323-31
references.pmid: 23946285
references.citation: Diabetes. 2012 Aug;61(8):2105-13
references.pmid: 22698914
references.citation: J Clin Invest. 2013 Dec;123(12):5082-97
references.pmid: 24177422
references.citation: Am J Physiol Renal Physiol. 2011 May;300(5):F1203-13
references.pmid: 21367915
references.citation: Cell Commun Signal. 2013;11:51
references.pmid: 23899007
references.citation: Cell. 1997 Nov 14;91(4):439-42
references.pmid: 9390552
references.citation: J Biol Chem. 2005 Nov 25;280(47):39616-26
references.pmid: 16135519
references.citation: J Clin Invest. 1998 Dec 1;102(11):1900-10
references.pmid: 9835614
references.citation: Hypertension. 1992 Feb;19(2 Suppl):II168-75
references.pmid: 1735573
references.citation: Oxid Med Cell Longev. 2013;2013:462361
references.pmid: 23840917
references.citation: Exp Cell Res. 2003 Jan 15;282(2):90-100
references.pmid: 12531695
references.citation: Mol Biol Cell. 2014 Aug 15;25(16):2342-50
references.pmid: 24943838
references.citation: Kidney Int. 2000 Jan;57(1):167-82
references.pmid: 10620198
references.citation: J Biol Chem. 2005 Aug 26;280(34):30201-5
references.pmid: 15983040
references.citation: BMC Nephrol. 2014;15:135
references.pmid: 25142208
references.citation: J Am Soc Nephrol. 2011 Jan;22(1):21-7
references.pmid: 21209251
references.citation: J Clin Invest. 2014 Jun;124(6):2299-306
references.pmid: 24892703
references.citation: J Am Soc Nephrol. 2012 Dec;23(12):1967-76
references.pmid: 23100220
references.citation: Curr Opin Nephrol Hypertens. 2006 May;15(3):250-7
references.pmid: 16609291
references.citation: Am J Physiol Renal Physiol. 2012 Jun 1;302(11):F1351-61
references.pmid: 22492945
references.citation: J Am Soc Nephrol. 2013 Oct;24(10):1512-8
references.pmid: 23970124