Fluvastatin reduces renal fibroblast proliferation and production of type III collagen: therapeutic implications for tubulointerstitial fibrosis.
BACKGROUND
Accumulating evidence suggests that hydroxymethylglutaryl-CoA reductase inhibitors have many biological effects beyond reducing cholesterol synthesis. In a mouse model of renal interstitial fibrosis induced by unilateral ureteral obstruction, fluvastatin, one of the lipophilic hydroxymethylglutaryl-CoA reductase inhibitors, was shown to ameliorate fibrosis.


METHODS
In the present study, we examined the direct effects of fluvastatin on proliferation, matrix and growth factor production by rat kidney fibroblasts (NRK-49F cells).


RESULTS
Treatment with fluvastatin reduced proliferation of NRK-49F cells in a dose-dependent manner. The addition of mevalonate or geranylgeranyl pyrophosphate but not farnesyl pyrophosphate to the culture medium almost completely abolished the effect of fluvastatin. Moreover, fluvastatin treatment decreased the expression of activated Rho in NRK-49F cells suggesting that fluvastatin may decrease cell growth through blocking the activation of Rho. The majority of fluvastatin-treated cells were arrested at the G1 phase, associated with down-regulation of cyclin A and up-regulation of cyclin-dependent kinase inhibitor p27kip1, indicating that cell cycle modulation is an important mechanism. Fluvastatin significantly decreased messenger RNA expression of type III collagen and connective tissue growth factor.


CONCLUSIONS
Taken together, it is suggested that fluvastatin may prevent tubulointerstitial fibrosis in a variety of progressive renal diseases by inhibiting proliferation of interstitial fibroblasts and their matrix synthesis.
Ikeuchi
Hidekazu
H
Department of Medicine and Clinical Science, Gunma Graduate School of Medicine, Maebashi, Japan.
Kuroiwa
Takashi
T
Yamashita
Shin
S
Hiramatsu
Noriyuki
N
Maeshima
Akito
A
Kaneko
Yoriaki
Y
Hiromura
Keiju
K
Ueki
Kazue
K
Nojima
Yoshihisa
Y
D000209:Acute-Phase Proteins / Q000096:biosynthesis; D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D024061:Collagen Type III / Q000096:biosynthesis*; D055513:Connective Tissue Growth Factor; D019925:Cyclin A / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005229:Fatty Acids, Monounsaturated / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects*; D005355:Fibrosis / Q000188:drug therapy*; D000077340:Fluvastatin; D016193:G1 Phase / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D007211:Indoles / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008798:Mevalonic Acid / Q000494:pharmacology; D009395:Nephritis, Interstitial / Q000188:drug therapy*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D051381:Rats; D012717:Sesquiterpenes; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
D000209:Acute-Phase Proteins; C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D024061:Collagen Type III; D019925:Cyclin A; D005229:Fatty Acids, Monounsaturated; D017874:Immediate-Early Proteins; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D025521:Tumor Suppressor Proteins; C010781:acute-phase protein rho; D055513:Connective Tissue Growth Factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077340:Fluvastatin; C004808:farnesyl pyrophosphate; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid