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 microg/ml) induced a significant decrease in ET-1 mRNA expression (minimum 51.8+/-3.8% of control; P<0.001) in HUVEC and RAEC. After a 48 h incubation with MPA (1-50 microg/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.
Haug
Cornelia
C
Institute of Clinical Chemistry, University Hospital Ulm, Robert-Koch-Strasse 8, D-89070 Ulm, Germany. cornelia.haug@medizin.uni-ulm.de
Schmid-Kotsas
Alexandra
A
Linder
Theresia
T
Jehle
Peter M
PM
Bachem
Max G
MG
Gruenert
Adolf
A
Rozdzinski
Eva
E
D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D019332:Endothelin-1 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000378:metabolism; D009173:Mycophenolic Acid / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D004247:DNA; D007770:L-Lactate Dehydrogenase; D009173:Mycophenolic Acid