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 calcineu rin, one of the serine-threonine phosphatases. Recent studies have shown th at NFAT also is expressed in nonlymphoid cells and plays an important role in various cell functions. It is widely known that treatment with cyclospor in A (CsA), which can inhibit calcineurin/NFAT signaling, results in glomer ular dysfunction characterized by a decrease of GFR or glomerulosclerosis, suggesting that NFAT might regulate the glomerular function. However, the p recise function of NFAT in glomerular cells remains to be clarified. Herein , evidence has been produced that NFAT2/NFATc, one of five known NFAT isofo rms, is expressed in glomerular mesangial cells. Stimulation of mesangial c ells with endothelin-1 caused translocation of NFAT2 into the nucleus with a concomitant increase in NFAT2 DNA-binding activity, both of which were in hibited by CsA. Furthermore, CsA inhibited endothelin-1-induced cyclooxygen ase-2 (COX-2) expression in mesangial cells. NFAT2 bound directly to the GG AAA 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 mes angial cells. These results will contribute to evaluation of the precise ro les of NFAT in glomerular functions and the CsA-induced nephrotoxicity.