Endothelin-1 induces cyclooxygenase-2 expression via nuclear factor of activated T-cell transcription factor in glomerular mesangial cells.
Nuclear factor of activated T cells (NFAT) originally was identified as a T-cell-specific transcription factor whose activity is regulated by calcineurin, one of the serine-threonine phosphatases. Recent studies have shown that NFAT also is expressed in nonlymphoid cells and plays an important role in various cell functions. It is widely known that treatment with cyclosporin A (CsA), which can inhibit calcineurin/NFAT signaling, results in glomerular dysfunction characterized by a decrease of GFR or glomerulosclerosis, suggesting that NFAT might regulate the glomerular function. However, the precise function of NFAT in glomerular cells remains to be clarified. Herein, evidence has been produced that NFAT2/NFATc, one of five known NFAT isoforms, is expressed in glomerular mesangial cells. Stimulation of mesangial cells with endothelin-1 caused translocation of NFAT2 into the nucleus with a concomitant increase in NFAT2 DNA-binding activity, both of which were inhibited by CsA. Furthermore, CsA inhibited endothelin-1-induced cyclooxygenase-2 (COX-2) expression in mesangial cells. NFAT2 bound directly to the GGAAA sequence, which is the minimal consensus sequence for NFAT binding, in a promoter region of rat COX-2 gene, and it enhanced the reporter activity of rat COX-2 promoter in mesangial cells. These findings provide the first evidence that NFAT2 is expressed and regulates COX-2 gene expression in mesangial cells. These results will contribute to evaluation of the precise roles of NFAT in glomerular functions and the CsA-induced nephrotoxicity.
Sugimoto
Toshiro
T
The Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga.|Japan Foundation for Aging and Health, Higashiura Cho, Aichi, Japan.
Haneda
Masakazu
M
The Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga.
Sawano
Hirotaka
H
The Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga.
Isshiki
Keiji
K
The Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga.
Maeda
Shiro
S
The Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga.
Koya
Daisuke
D
The Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga.
Inoki
Ken
K
The Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga.
Yasuda
Hitoshi
H
The Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga.
Kashiwagi
Atsunori
A
The Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga.
Kikkawa
Ryuichi
R
The Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga.
D000818:Animals; D001483:Base Sequence / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology*; D004357:Drug Synergism; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000502:physiology*
D004268:DNA-Binding Proteins; D019332:Endothelin-1; D007166:Immunosuppressive Agents; D007476:Ionophores; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D016572:Cyclosporine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D002118:Calcium