Nephrol Dial Transplant (2001) 16: 2310-2316
© 2001 European Renal Association-European Dialysis and Transplant Association
Influence of hepatocyte growth factor, epidermal growth factor, and mycophenolic acid on endothelin-1 synthesis in human endothelial cells
1 Institute of Clinical Chemistry and 2 Department of Medical Microbiology, University Hospital, Ulm, Germany
Background. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide which plays an important pathophysiological role in ischaemic renal failure and drug-induced renal injury such as cyclosporin A (CsA)- and tacrolimus-associated nephrotoxicity. In contrast, hepatocyte growth factor (HGF) and epidermal growth factor (EGF) seem to accelerate renal regeneration after ischaemic and drug-induced renal injury. This study aimed to investigate the influence of HGF and EGF on ET-1 synthesis in cultured human umbilical vein endothelial cells (HUVEC) and renal artery endothelial cells (RAEC). In addition, we have investigated whether mycophenolic acid (MPA), a new immunosuppressive drug, which in contrast to CsA and tacrolimus lacks nephrotoxic side effects, modulates ET-1 synthesis in endothelial cells.
Methods. ET-1 release was measured with a specific enzyme-linked immunosorbent assay. ET-1 mRNA expression was investigated by reverse transcription polymerase chain reaction.
Results. HGF and EGF (0.001-10 nM) exerted a significant concentration-dependent inhibitory effect on ET-1 release by HUVEC and RAEC (minimum 56.1±4.3% of control, n=6, mean±SE). The suppressive effect of HGF and EGF on ET-1 synthesis was dose-dependently antagonized by the tyrosine kinase inhibitors tyrphostin AG1478, lavendustin A and methyl 2,5-dihydroxycinnamate. Incubation of HUVEC and RAEC with MPA (2.5, 10, 25, and 50 µg/ml) for 3–5 h induced a significant reduction of ET-1 mRNA expression. After 48 h incubation with MPA (1–50 µg/ml) a significant decrease of ET-1 release and DNA content per culture well was observed, whereas ET-1 release referred to the DNA content in the corresponding culture well did not differ significantly from controls.
Conclusions. The present findings demonstrate that HGF and EGF reduce ET-1 synthesis in endothelial cells via their receptor tyrosine kinase activity and suggest that the renoprotective effects of HGF and EGF might be linked to their inhibitory action on ET-1 synthesis. This study also provides evidence that, in contrast to CsA and tacrolimus, MPA does not stimulate ET-1 synthesis. This might explain the clinical observation that renal function often improves when CsA or tacrolimus is replaced by mycophenolate mofetil.
Keywords: endothelin-1; endothelial cells; epidermal growth factor; hepatocyte growth factor; mycophenolic acid; tyrosine kinase inhibitors
Correspondence and offprint requests to: Dr Cornelia Haug, Institute of Clinical Chemistry, University Hospital Ulm, Robert-Koch-Strasse 8, D-89070 Ulm, Germany. Email: cornelia.haug{at}medizin.uni\|[hyphen]\|ulm.de
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  P. Biswas, A. Roy, R. Gong, A. Yango, E. Tolbert, J. Centracchio, and L. D. Dworkin Hepatocyte growth factor induces an endothelin-mediated decline in glomerular filtration rate Am J Physiol Renal Physiol, January 1, 2005; 288(1): F8 - F15. [Abstract] [Full Text] [PDF]
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