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- Title
Homocysteine enhances TIMP-1 expression and cell proliferation associated with NADH oxidase in rat mesangial cells.
- Authors
Yang, Zhi-Zhang; Zou, Ai-Ping
- Abstract
Homocysteine enhances TIMP-1 expression and cell proliferation associated with NADH oxidase in rat mesangial cells. Background. Recent studies in our laboratory demonstrated that chronic hyperhomocysteinemia (hHcys) induced glomerular sclerosis. The mechanism mediating hHcys-induced glomerular damage remains unknown. The present study was designed to test a hypothesis that homocysteine (Hcys) increases the &formmu0; production by nicotinamide adenine dinucleotide (NADH) oxidase and thereby stimulates the formation of tissue inhibitor of metalloproteinase (TIMP-1) in rat mesangial cells, consequently leads to glomerulosclerosis. Methods. Rat mesangial cells were incubated with L-homocysteine (L-Hcys) to determine the effects of Hcys on cell proliferation and metabolism of extracellular matrix (ECM). Northern blot, Western blot, oligonucleotide transfection, measurements of NADH oxidase activity and &formmu1; levels, and cell proliferation assay were performed. Results. In cultured rat mesangial cells, treatment with L-Hcys (40 to 160 μmol/L) markedly increased the mRNA levels of TIMP-1 and Gp91 and led to accumulation of collagen I, which were accompanied by enhanced cell proliferation and NADH oxidase activity in mesangial cells. These Hcys-induced biochemical and functional changes were substantially blocked by a NADH oxidase inhibitor, diphenylene iodonium chloride (DPI) or a superoxide dismutase (SOD) mimetic, hydroxyl-tetramethylpiperidin-oxyl (TEMPOL). Moreover, blockade of NADH oxidase subunit, phox22, by its antisense oligodeoxynucleotide also eliminated the increase in NADH oxidase activity induced by L-Hcys. Conclusion. These results indicate that Hcys-induced alterations of ECM metabolism in mesangial cells are associated with enhanced NADH oxidase activity and that oxidative stress-stimulated up-regulation of TIMP-1 may play an important role in the deposition of collagen or ECM elements in the glomeruli during hHcys.
- Subjects
HOMOCYSTEINE; METALLOPROTEINASES; CELL proliferation; NAD (Coenzyme)
- Publication
Kidney International, 2003, Vol 63, Issue 3, p1012
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1046/j.1523-1755.2003.00825.x