RGD Reference Report - Homocysteine enhances TIMP-1 expression and cell proliferation associated with NADH oxidase in rat mesangial cells. - Rat Genome Database

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Homocysteine enhances TIMP-1 expression and cell proliferation associated with NADH oxidase in rat mesangial cells.

Authors: Yang, ZZ  Zou, AP 
Citation: Yang ZZ and Zou AP, Kidney Int. 2003 Mar;63(3):1012-20.
RGD ID: 11040676
Pubmed: PMID:12631082   (View Abstract at PubMed)
DOI: DOI:10.1046/j.1523-1755.2003.00825.x   (Journal Full-text)

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 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 levels, and cell proliferation assay were performed. RESULTS: In cultured rat mesangial cells, treatment with L-Hcys (40 to 160 micromol/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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CybaRatpositive regulation of NAD(P)H oxidase activity  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyba  (cytochrome b-245 alpha chain)


Additional Information