NMDA receptor-mediated activation of NADPH oxidase and glomerulosclerosis in hyperhomocysteinemic rats.
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.
Zhang
Chun
C
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Yi
Fan
F
Xia
Min
M
Boini
Krishna M
KM
Zhu
Qing
Q
Laperle
Laura A
LA
Abais
Justine M
JM
Brimson
Christopher A
CA
Li
Pin-Lan
PL
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
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
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