title: NMDA receptor-mediated activation of NADPH oxidase and glomerulosclerosis in hyperhomocysteinemic rats.
abstract: This study investigated the role of NMDA receptor in hyperhomocyteinemia (hHcys)-induced NADPH oxidase (Nox) activation and glomerulosclerosis. Sprague-Dawley rats were fed a folate-free (FF) diet to produce hHcys, and a NMDA receptor antagonist, MK-801, was administrated. Rats fed the FF diet exhibited significantly increased plasma homocysteine levels, upregulated NMDA receptor expression, enhanced Nox activity and Nox-dependent O(2)(.-) production in the glomeruli, which were accompanied by remarkable glomerulosclerosis. MK-801 treatment significantly inhibited Nox-dependent O(2)(.-) production induced by hHcys and reduced glomerular damage index as compared with vehicle-treated hHcys rats. Correspondingly, glomerular deposition of extracellular matrix components in hHcys rats was ameliorated by the administration of MK-801. Additionally, hHcys induced an increase in tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and a decrease in matrix metalloproteinase (MMP)-1 and MMP-9 activities, all of which were abolished by MK-801 treatment. In vitro studies showed that homocysteine increased Nox-dependent O(2)(.-) generation in rat mesangial cells, which was blocked by MK-801. Pretreatment with MK-801 also reversed homocysteine-induced decrease in MMP-1 activity and increase in TIMP-1 expression. These results support the view that the NMDA receptor may mediate Nox activation in the kidney during hHcys and thereby play a critical role in the development of hHcys-induced glomerulosclerosis.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Boini
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.forename: Laura A
authors.initials: LA
authors.lastname: Laperle
authors.forename: Justine M
authors.initials: JM
authors.lastname: Abais
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Brimson
authors.forename: Pin-Lan
authors.initials: PL
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020138:Hyperhomocysteinemia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016202:N-Methylaspartate / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D019715:Tissue Inhibitor of Metalloproteinase-1; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D005492:Folic Acid; D019255:NADPH Oxidases; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1
references.citation: Kidney Int. 2006 Jul;70(1):88-96
references.pmid: 16688115
references.citation: Kidney Int. 1999 Apr;55(4):1470-5
references.pmid: 10201012
references.citation: J Neurosci. 1995 Oct;15(10):6377-88
references.pmid: 7472402
references.citation: N Engl J Med. 2006 Apr 13;354(15):1578-88
references.pmid: 16531614
references.citation: J Physiol (Paris). 1979;75(6):641-54
references.pmid: 232719
references.citation: J Neurochem. 2009 Aug;110(3):1095-106
references.pmid: 19508427
references.citation: Cell Physiol Biochem. 2007;20(6):909-18
references.pmid: 17982273
references.citation: J Neurosci. 2000 Nov 1;20(21):8005-11
references.pmid: 11050121
references.citation: Kidney Int. 2007 Apr;71(8):755-63
references.pmid: 17290295
references.citation: Neuroreport. 2000 Aug 21;11(12):2749-52
references.pmid: 10976956
references.citation: Am J Physiol Renal Physiol. 2009 May;296(5):F976-82
references.pmid: 19279130
references.citation: Kidney Int. 2004 Nov;66(5):1977-87
references.pmid: 15496169
references.citation: Am J Physiol Renal Physiol. 2009 Aug;297(2):F410-9
references.pmid: 19474193
references.citation: Thromb Res. 2010 Feb;125(2):e23-32
references.pmid: 19766294
references.citation: Kidney Int. 2004 Jul;66(1):167-76
references.pmid: 15200423
references.citation: J Am Soc Nephrol. 2000 Jan;11(1):134-137
references.pmid: 10616849
references.citation: Biochem Biophys Res Commun. 1998 Oct 29;251(3):669-76
references.pmid: 9790967
references.citation: Kidney Int. 2004 Sep;66(3):1090-8
references.pmid: 15327403
references.citation: Am J Nephrol. 2007;27(3):262-8
references.pmid: 17396029
references.citation: Antioxid Redox Signal. 2009 Jan;11(1):25-33
references.pmid: 18837652
references.citation: Eur J Pharmacol. 2006 Sep 28;546(1-3):109-19
references.pmid: 16908017
references.citation: J Am Soc Nephrol. 2002 May;13(5):1381-4
references.pmid: 11961027
references.citation: J Pept Sci. 2004 May;10(5):229-48
references.pmid: 15160835
references.citation: Semin Immunopathol. 2007 Nov;29(4):385-95
references.pmid: 17828397
references.citation: Free Radic Biol Med. 2010 Apr 15;48(8):1109-17
references.pmid: 20116427
references.citation: Exp Neurol. 1994 Dec;130(2):344-50
references.pmid: 7867764
references.citation: Circulation. 1996 Dec 1;94(11):2743-8
references.pmid: 8941098
references.citation: Hypertension. 2009 Jan;53(1):90-6
references.pmid: 19029489
references.citation: Circ Res. 2008 May 9;102(9):1101-8
references.pmid: 18356541
references.citation: Nature. 1991 Nov 7;354(6348):31-7
references.pmid: 1834949
references.citation: J Vasc Surg. 2005 May;41(5):853-60
references.pmid: 15886671
references.citation: J Am Soc Nephrol. 2009 Sep;20(9):1929-40
references.pmid: 19578006
references.citation: Science. 1992 May 22;256(5060):1217-21
references.pmid: 1350383
references.citation: J Biol Chem. 1993 Feb 5;268(4):2836-43
references.pmid: 8428958
references.citation: Am J Physiol Renal Physiol. 2008 Jun;294(6):F1433-40
references.pmid: 18272600
references.citation: Kidney Int. 2003 Mar;63(3):1012-20
references.pmid: 12631082
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Oct;283(4):R964-71
references.pmid: 12228067
references.citation: Kidney Int. 2004 Aug;66(2):733-45
references.pmid: 15253728