LOVASTATIN MODULATES IN-VIVO AND IN-VITRO THE PLASMINOGEN-ACTIVATOR PLASMIN SYSTEM OF RAT PROXIMAL TUBULAR CELLS - ROLE OF GERANYLGERANYLATION AND RHO-PROTEIN

Interstitial fibrosis is one of the most deleterious events during the progression of renal deterioration after renal mass reduction. In viv o, hydroxymethylglutaryl CoA reductase inhibitors (HRI) were shown to reduce progression of glomerulosclerosis, but the mechanisms are still unclear. The present study investigates, in vivo, whether lovastatin, a potent. HRI, was able to modulate the plasminogen-plasmin pathway, one of the most efficient systems involved in extracellular matrix rem odeling, and characterizes in vitro the cellular mechanisms of these e ffects. Proximal tubules freshly isolated from rats treated for 2 d wi th lovastatin (4 mg/kg per d) showed:increased tissue-type plasminogen activator (tPA) and urokinase (uPA) activities and antigens. Incubati on with lovastatin (5 mu M) Of proximal tubules isolated from untreate d rats induced an increase in tPA and uPA and a decrease in plasminoge n activator inhibitor-1 (PAI-1) activities. In vitro, supernatants, cy tosols, and membranes of renal proximal tubular cells in primary cultu res had no detectable uPA activity, and lovastatin (0.1 to 10 mu M) in duced an increase in tPA and a decrease in PAI-1 activities and antige ns. These effects were reversed by mevalonate and geranylgeranyl-pyrop hosphate (GGPP) but not by farnesyl-pyrophosphate or LDL cholesterol. C3 exoenzyme, an inhibitor of the geranylgeranylated-activated Rho pro tein, reproduced the effect of lovastatin on tPA and PAI-1 activity an d blocked its reversion by GGPP. The effect of lovastatin was associat ed with a disruption of cellular actin stress fibers, which was revers ed by GGPP and reproduced by C3 exoenzyme. In conclusion, HRI can modi fy the fibrinolytic potential of proximal tubules, most likely via inh ibition of geranylgeranylated Rho protein and disruption of the cytosk eleton. The resulting increase of proteolytic activity of tubular cell s may serve to prevent extracellular matrix deposition and renal inter stitial fibrosis.