Nephrology Dialysis Transplantation, Vol 14, Issue 1 58-63, Copyright © 1999 by Oxford University Press
I Hauser, L Renders, H Radeke, R Sterzel and M Goppelt-Struebe
Background: Mycophenolate mofetil (MMF) is used for
immunosuppression after renal transplantation because it reduces lymphocyte
proliferation by inhibiting inosine monophosphate dehydrogenase (IMPDH) in
lymphocytes and GTP biosynthesis. In the present study we asked if
therapeutic concentrations of MMF might interfere with mesangial cell (MC)
proliferation which is involved in inflammatory proliferative glomerular
diseases. Methods: Rat and human MCs were
growth-arrested by withdrawal of fetal calf serum (FCS) and stimulated by
addition of FCS, platelet-derived growth factor (PDGF) of lysophosphatidic
acid (LPA). Different concentrations of MMF (0.019-10 &mgr;M) were
added concomitantly in the presence or absence of guanosine. MC
proliferation was determined by [3H}thymidine
incorporation. Cell viability was assessed by trypan blue exclusion.
Apoptotic nuclei were stained using the Hoechst dye H33258. Cytosolic free
Ca2+ concentrations were determined with the
fluorescent calcium chelator fura-2-AM. Results: MMF
inhibited mitogen-induced rat MC proliferation with an IC50 of
0.45±0.13 &mgr;M. Human MCs proved to be even more sensitive
(IC50 0.19±0.06 &mgr;M). Inhibition of MC proliferation was
reversible and not accompanied by cellular necrosis or apoptosis. Addition
of guanosine prevented antiproliferative effect of MMF, indicating that
inhibition of IMPDH is responsible for decreased MC proliferation. Early
signalling events of GTP-binding-protein-coupled receptors, such as changes
in intracellular Ca2+ levels were not affected by
MMF. Conclusions: The results show that MMF has a
concentration-dependent antiproliferative effect on cultures MCs in the
therapeutic range, which might be a rationale for the use of this drug in
the treatment of mesangial proliferative glomerulonephritis. Key
words: glomerulonephritis; immunosuppressive therapy; inosine
monophosphate dehydrogenase; mesangial cell proliferation; mycophenolate
mofetil; purine synthesis
ORIGINAL ARTICLES
Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion
Department of Nephrology, University of Frankfurt/Main, Frankfurt/Main, Germany; Department of Medicine IV, University of Erlangen-Nurnberg, Erlangen, Germany; Department of Pharmacology, Medizinische Hochschule Hannover, Hannover, Germany; Corresponding author at: Medizinische Klinik IV, Funktionsbereich Nephrologie, Universitatsklinik Frankfurt/Main, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
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