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Activation of renal NMDA by Hcy causes ECM remodeling by modulating MMP/TIMP axis
Author(s) -
Gargoum Riyad Rachid,
Rosenberger Dorothea,
Abe Oluwasegun,
Lawal Rasheed,
Sen Utpal,
Tyagi Suresh
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb704
Subject(s) - hyperhomocysteinemia , nmda receptor , medicine , endocrinology , matrix metalloproteinase , homocysteine , chemistry , receptor
Elevated levels of homocysteine (Hcy) also known as hyperhomocysteinemia (HHcy) is one of the major causes of end‐stage renal disease. Disruptions in glomerular extracellular matrix (ECM) resulting from remodeling by activated matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) is the primary cause of impaired renal filtration. Although Hcy is a ligand to the ionotropic N‐methyl D‐aspartate (NMDA) receptor and the NMDA‐R1 subunit has been shown to be involved in renovascular calcium‐mediated toxicity, the mechanism of this toxicity is unclear. To test the hypothesis that HHcy causes glomerulosclerosis in part by causing imbalances in the MMP/TIMP axis, we created HHcy in mice and treated them with or without 0.5mg/kg MK801 (NMDA receptor blocker) by intraperitoneal injection for the last 10 days. Mice were grouped into: 1. Wild type (WT), 2. HHcy, 3. WT+MK801, 4. HHcy+MK801. The kidneys were isolated, weighed and homogenized. To measure NMDA‐R1, MMP‐2 and‐9, TIMP‐1, ‐3, and ‐4, western blot analysis was performed. The results suggest that homocysteine is involved in modulating the MMP/TIMP axis by changes in TIMP‐1, and ‐4 in a manner that is reversed by MK801.