Effect of lipid-lowering strategies on tubular cell biology.
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.
Department of Physiology, Faculté de Médecine Xavier-Bichat, Université Denis-Diderot, Paris, France. francois.vrtovsnik@bch.ap-hop-paris.fr
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Vrtovsnik
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Essig
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Iimura
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Friedlander
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010960:Plasminogen Activators / Q000187:drug effects / Q000378:metabolism
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010960:Plasminogen Activators