TY - JOUR
T1 - Lovastatin inhibits proliferation of rat mesangial cells
AU - O'Donnell, Michael P.
AU - Kasiske, Bertram L.
AU - Kim, Youngki
AU - Atluru, Durgaprasadarao
AU - Keane, William F.
PY - 1993/1
Y1 - 1993/1
N2 - Products of intracellular mevalonate metabolism are essential for cell growth and proliferation. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, blocks the formation of mevalonate and its metabolites, and has been shown to inhibit proliferation of several cell types. In vivo, lovastatin has reduced mesangial cellularity and glomerular injury in experimental renal disease. In this study, we investigated the effects of lovastatin on DNA replication and proliferation in rat glomerular mesangial cells. Growth-arrested mesangial cells were exposed to medium containing 10% fetal bovine serum to stimulate mitogenesis. Lovastatin (1-20 μM) caused a significant (P < 0.05) dose-dependent reduction in DNA synthesis ([3H]thymidine incorporation) which was completely prevented in the presence of exogenous mevalonate (100 μM). Lovastatin (1 μM) inhibited cell proliferation by 90% over a 5-d period, and this was largely overcome by added mevalonate. Exogenous low density lipoprotein (100 μg/ml) did not prevent lovastatin inhibition of DNA synthesis. The isoprenoid end product isopentenyl adenine (5 or 50 μM) had little effect on DNA synthesis and cell proliferation in lovastatinblocked cells. By contrast, the isoprenoid farnesol (5 μM) largely prevented lovastatin inhibition of DNA synthesis. We conclude that mevalonate metabolism is essential for mesangial cell proliferation, possibly through the production of the isoprenoid farnesol. Moreover, the action of lovastatin to reduce experimental glomerular injury may involve a direct effect on mesangial cells.
AB - Products of intracellular mevalonate metabolism are essential for cell growth and proliferation. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, blocks the formation of mevalonate and its metabolites, and has been shown to inhibit proliferation of several cell types. In vivo, lovastatin has reduced mesangial cellularity and glomerular injury in experimental renal disease. In this study, we investigated the effects of lovastatin on DNA replication and proliferation in rat glomerular mesangial cells. Growth-arrested mesangial cells were exposed to medium containing 10% fetal bovine serum to stimulate mitogenesis. Lovastatin (1-20 μM) caused a significant (P < 0.05) dose-dependent reduction in DNA synthesis ([3H]thymidine incorporation) which was completely prevented in the presence of exogenous mevalonate (100 μM). Lovastatin (1 μM) inhibited cell proliferation by 90% over a 5-d period, and this was largely overcome by added mevalonate. Exogenous low density lipoprotein (100 μg/ml) did not prevent lovastatin inhibition of DNA synthesis. The isoprenoid end product isopentenyl adenine (5 or 50 μM) had little effect on DNA synthesis and cell proliferation in lovastatinblocked cells. By contrast, the isoprenoid farnesol (5 μM) largely prevented lovastatin inhibition of DNA synthesis. We conclude that mevalonate metabolism is essential for mesangial cell proliferation, possibly through the production of the isoprenoid farnesol. Moreover, the action of lovastatin to reduce experimental glomerular injury may involve a direct effect on mesangial cells.
KW - Farnesol
KW - Glomerulosclerosis
KW - Glomerulus
KW - Isoprenoids
KW - Mevalonate
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M3 - Article
C2 - 8423236
AN - SCOPUS:0027469404
SN - 0021-9738
VL - 91
SP - 83
EP - 87
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -