title: Collagen secretion and growth of mesangial cells require geranylgeranylpyrophosphate.
abstract: BACKGROUND
  The mevalonate pathway is important for the biosynthesis of isoprenoids such as geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate, 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. However, the effect of HMG-CoA reductase inhibitor on mesangial cell function has not been fully understood. This investigation was performed to elucidate the role of a mevalonate metabolite(s) in mesangial cell proliferation and extracellular matrix accumulation.
  
  
  METHODS
  Cycling or quiescent human mesangial cells were incubated in RPMI 1640 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, mRNA expression, and [3H]thymidine incorporation were 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 the G1 to S phase transition of FCS-stimulated mesangial cells. Mevalonate reversed these inhibitory effects of pravastatin completely. Among two major metabolites of mevalonate, GGPP and farnesylpyrophosphate, only GGPP reversed pravastatin-induced inhibition of type IV collagen secretion, DNA synthesis, and the G1 to S phase progression.
  
  
  CONCLUSIONS
  These results suggest that GGPP plays critical roles for the type IV collagen secretion and G1 to S phase transition in FCS-stimulated human mesangial cells.
authors.affiliation: Department of Internal Medicine, Sakura National Hospital, Chiba-city, Japan. mnishi@hosp.Sakura-nh.go.jp
authors.forename: M
authors.initials: M
authors.lastname: Nishimura
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Yasuda
authors.forename: S
authors.initials: S
authors.lastname: Kurakata
authors.forename: M
authors.initials: M
authors.lastname: Kitagawa
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: A
authors.initials: A
authors.lastname: Hirai
mesh_terms: D000818:Animals; D002417:Cattle / Q000097:blood / Q000196:embryology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D005312:Fetal Blood / Q000502:physiology; 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; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology