Cerivastatin inhibits proliferation of interleukin-1 beta-induced rat mesangial cells by enhanced formation of nitric oxide.
The antiproliferative effect of statins on mesangial cells could represent a new therapeutic approach in glomerulonephritis. We studied in rat mesangial cells whether the antiproliferative action of cerivastatin on mesangial cells may be mediated by mesangial nitric oxide (NO) formation due to the inducible NO synthase (iNOS) or by induction of cyclooxygenase-2. Mesangial cells were stimulated with interleukin-1 beta and treated with cerivastatin for 24 h. Cell proliferation was examined by bromodeoxy-uridine (BrdU) incorporation, and nitrite and prostaglandin production was measured in supernatants as a means for iNOS or cyclooxygenase-2 activity. iNOS and cyclooxygenase-2 expression was quantified by Northern and Western blot analyses. Cerivastatin (0.0625 microM) significantly inhibited DNA synthesis in interleukin-1 beta-stimulated mesangial cells without altering cell viability. Interleukin-1 beta-induced nitrite production was twofold increased by 0.05 microM cerivastatin, and this effect could be reversed by addition of 100 microM mevalonate. iNOS mRNA levels increased sixfold (33% of maximum) in cerivastatin-treated mesangial cells as compared with vehicle-treated controls (3.5% of maximum). iNOS and cyclooxygenase-2 protein expression increased threefold (iNOS: 2.77+/-0.53/cyclooxygenase-2: 3.49+/-1.25). The NOS inhibitors N-methyl-L-arginine (L-NMMA) and L-N6-(1-iminoethyl)lysine (L-NIL) reversed the antiproliferative effect of cerivastatin. The cyclooxygenase-2 inhibitor celecoxib did not alter DNA synthesis and iNOS or cyclooxygenase-2 expression, but blocked prostacyclin production in interleukin-1 beta and cerivastatin-treated mesangial cells. In conclusion, cerivastatin increased cytokine-induced iNOS and cyclooxygenase-2 expression, thus constituting NO-regulated growth inhibition of mesangial cells.
Blume
Cornelia
C
Klinik für Nephrologie und Rheumatologie Medizinische Einrichtungen, Heinrich-Heine-Universität, Moorenstrasse 5, 40225 Duesseldorf, Germany. hblume@cityweb.de
Sabuda-Widemann
Danuta
D
Pfeilschifter
Josef
J
Plum
Jörg
J
Schrör
K
K
Grabensee
Bernd
B
Beck
Karl-Friedrich
KF
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats
D006131:Growth Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D011725:Pyridines; D009569:Nitric Oxide; C086276:cerivastatin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases