The immunosuppressive drug mycophenolic acid reduces endothelin-1 synthesis in endothelial cells and renal epithelial cells

Several studies have demonstrated that endothelin-1 (ET-1) plays an important pathophysiological role in ischaemic renal failure and drug-induced renal injury, such as cyclosporine A (CsA)- and tacrolimus-associated nephrotoxicity. This study aimed to investigate whether the new immunosuppressive drug mycophenolic acid (MPA), which in contrast with CsA and tacrolimus lacks nephrotoxic side effects, modulates ET-1 synthesis in endothelial cells and renal epithelial cells. ET-1 release by cultured human umbilical vein endothelial cells (HUVEC), human renal artery endothelial cells (RAEC) and rabbit proximal tubule cells was measured with a specific ELISA. ET-1 mRNA expression was investigated by reverse transcription-PCR. MPA (2.5-50 mug/ml) induced a significant decrease in ET-1 m RNA expression (minimum 51.8 +/- 3.8% of control; P < 0.001) in HUVEC and RAEC. After a 48 h incubation with MPA (1-50 mu g/ml), a significant decrease in ET-1 release per culture well (minimum 56.8 +/- 1.7%; P < 0.001)and DNA content per culture well (minimum 58.7 +/- 1.9%; P < 0.001) was observed with HUVEC and RAEC, whereas ET-1 release referred to the DNA content in the corresponding culture well did not differ significantly from controls. In rabbit proximal tubule cells, ET-1 release referred to the cell number in the corresponding culture well was also reduced after incubation with MPA (minimum 86.2 +/- 2.4%; P < 0.05). This study provides evidence that, in contrast with CsA and tacrolimus, MPA does not stimulate ET-1 synthesis. The present results might explain the clinical observation that renal function often improves when CsA or tacrolimus is replaced by mycophenolate mofetil.