Effect of pravastatin on type IV collagen secretion and mesangial cell proliferation.
BACKGROUND
The mevalonate pathway is important for the biosynthesis of isoprenoids such as geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) as well as cholesterol. It has been reported that treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor ameliorates glomerular injury in several experimental models of progressive glomerular disease. The present investigation was performed to elucidate the role of mevalonate metabolites in mesangial cell proliferation and extracellular matrix accumulation.


METHODS
Cycling or quiescent human mesangial cells were incubated in RPMI1640 containing 10% heat-inactivated fetal calf serum (FCS) in the absence or presence of pravastatin, an inhibitor of HMG-CoA reductase, and mevalonate metabolites. Type IV collagen secretion and mRNA expression, [3H]-thymidine incorporation was measured. Cell cycle phases were monitored by flow cytometry.


RESULTS
Pravastatin inhibited FCS-stimulated type IV collagen secretion (IC50 = 210 microM) and mRNA expression. Pravastatin also inhibited FCS-stimulated [3H]-thymidine incorporation (IC50 = 430 microM). Analysis with flow cytometry revealed that pravastatin inhibited G1 to S phase transition of FCS-stimulated mesangial cells. Mevalonate reversed these inhibitory effects of pravastatin completely. Among two major metabolities of mevalonate, GGPP and FPP, only GGPP reversed pravastatin-induced inhibition of type IV collagen secretion, DNA synthesis and G1 to S phase progression.


CONCLUSIONS
The present results suggest that GGPP plays a critical role in the type IV collagen secretion and G1 to S phase transition in FCS-stimulated human mesangial cells.
Nishimura
M
M
Department of Internal Medicine, Sakura National Hospital, Japan. mnishi@snh.hosp.go.jp
Tanaka
T
T
Yasuda
T
T
Kurakata
S
S
Kitagawa
M
M
Yamada
K
K
Saito
Y
Y
Hirai
A
A
D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D012717:Sesquiterpenes
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D003094:Collagen; D004247:DNA; D017035:Pravastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid