F Vrtovsnik1, M Essig, O Iimura, G Friedlander. 1. Department of Physiology, Faculté de Médecine Xavier-Bichat, Université Denis-Diderot, Paris, France. francois.vrtovsnik@bch.ap-hop-paris.fr
Abstract
BACKGROUND: Interstitial fibrosis and the development of renal cysts are crucial phenomena in renal disease progression. While 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been shown to reduce the progression of several experimental nephropathies, the mechanism of their potential protective effect remaines unclear. METHODS: The antiproliferative, apoptotic, and fibrinolytic effects of HMG-CoA reductase inhibitors were assessed in primary cultured rat (rPTCs) and mouse proximal tubule cells (mPTCs), in isolated rat proximal tubules, and in vivo in 5/6 nephrectomized rats (Nx). RESULTS: In vitro, lovastatin inhibited rPTC proliferation in a manner selectively prevented by mevalonate, farnesyl-, or geranylgeranyl-pyrophosphate (FPP or GGPP). Lovastatin reduced membrane-bound p21ras and fetal calf serum-induced c-fos and c-jun protein expression. Gel shift assay showed that lovastatin reduced activated protein-1 (AP-1) binding activity. In vivo, lovastatin inhibited tubular cell proliferation after Nx, as measured by proliferative cell nuclear antigen staining. Lovastatin-treated mPTCs displayed nucleus cleavage and DNA ladder formation, which were prevented by GGPP. Like C3 exoenzyme, lovastatin induced actin filament disruption, which preceded evidence of apoptosis. Lovastatin increased tissue-type plasminogen activator (PA) and decreased PA inhibitor activities and antigens; these effects were prevented by mevalonate and GGPP but not FPP, and were reproduced by C3 exoenzyme in a manner insensitive to GGPP. CONCLUSIONS: HMG-CoA reductase inhibitors decreased proliferation, increased apoptosis, and enhanced fibrinolytic activity of renal tubular cells via modulation of different isoprenylated proteins. These effects could participate to reduce the progression of renal diseases.
BACKGROUND: Interstitial fibrosis and the development of renal cysts are crucial phenomena in renal disease progression. While 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been shown to reduce the progression of several experimental nephropathies, the mechanism of their potential protective effect remaines unclear. METHODS: The antiproliferative, apoptotic, and fibrinolytic effects of HMG-CoA reductase inhibitors were assessed in primary cultured rat (rPTCs) and mouse proximal tubule cells (mPTCs), in isolated rat proximal tubules, and in vivo in 5/6 nephrectomized rats (Nx). RESULTS: In vitro, lovastatin inhibited rPTC proliferation in a manner selectively prevented by mevalonate, farnesyl-, or geranylgeranyl-pyrophosphate (FPP or GGPP). Lovastatin reduced membrane-bound p21ras and fetal calf serum-induced c-fos and c-jun protein expression. Gel shift assay showed that lovastatin reduced activated protein-1 (AP-1) binding activity. In vivo, lovastatin inhibited tubular cell proliferation after Nx, as measured by proliferative cell nuclear antigen staining. Lovastatin-treated mPTCs displayed nucleus cleavage and DNA ladder formation, which were prevented by GGPP. Like C3 exoenzyme, lovastatin induced actin filament disruption, which preceded evidence of apoptosis. Lovastatin increased tissue-type plasminogen activator (PA) and decreased PA inhibitor activities and antigens; these effects were prevented by mevalonate and GGPP but not FPP, and were reproduced by C3 exoenzyme in a manner insensitive to GGPP. CONCLUSIONS: HMG-CoA reductase inhibitors decreased proliferation, increased apoptosis, and enhanced fibrinolytic activity of renal tubular cells via modulation of different isoprenylated proteins. These effects could participate to reduce the progression of renal diseases.