Effect of lipid-lowering strategies on tubular cell biology

Background Interstitial fibrosis and the development of renal cysts are cru cial phenomena in renal disease progression. While 3-hydroxy-3-methylglutar yl coenzyme A (HMG-CoA) reductase inhibitors has been shown to reduce the p rogression of several experimental nephropathies, the mechanism of their po tential 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 sele ctively prevented by mevalonate, farnesyl-, or geranylgeranyl-pyrophosphate (FPP or GGPP), Lovastatin reduced membrane-bound p21(ras) and fetal calf s erum-induced c-fos and c-jun protein expression. Gel shift assay showed tha t lovastatin reduced activated protein-1 (AP-1) binding activity. In vivo, lovastatin inhibited tubular cell proliferation after Ns, as measured by pr oliferative cell nuclear antigen staining. Lovastatin-treated mPTCs display ed nucleus cleavage and DNA ladder formation, which were prevented by GGPP. Like C3 exoenzyme, lovastatin induced actin filament disruption, which pre ceded evidence of apoptosis. Lovastatin increased tissue-type plasminogen a ctivator (PA) and decreased PA inhibitor activities and antigens; these eff ects 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, increase d apoptosis. and enhanced fibrinolytic activity of renal tubular cells via modulation of different isoprenylated proteins. These effects could partici pate to reduce the progression of renal diseases.