Effects of lipids on the pathogenesis of progressive renal failure: role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in the prevention of glomerulosclerosis.
Increasing experimental evidence suggests that lipids might be important modulators in progressive glomerulosclerosis. The inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have demonstrated beneficial effects in different models of progressive renal failure. Monocyte infiltration, mesangial cell proliferation and mesangial matrix expansion have been shown to be early events in the process of glomerulosclerosis that can be lessened by HMG-CoA reductase inhibition. Recent experimental data suggest that these agents may also have glomerular protective effects independent of a reduction in circulating lipids. In vitro, lovastatin has been shown to downregulate mesangial cell production of monocyte chemoattractant protein-1 and colony-stimulating factor. In addition, HMG-CoA reductase inhibitors can directly reduce mesangial cell proliferation. These effects appear related to the ability of this class of agents to inhibit mesangial cell formation of intermediates of cholesterol formation, the nonsterol isoprenoids. Although low density lipoprotein cholesterol can induce mesangial cells to increase synthesis of matrix proteins, e.g., type-IV collagen, we have shown that lovastatin does not directly influence mesangial cell type-IV collagen metabolism. Thus, prevention of mesangial matrix expansion in vivo with type-IV collagen by HMG-CoA reductase inhibitors could be related to an indirect mechanism related to inhibition of monocyte influx into the glomerulus. Alternatively, a direct effect of these agents, through their cholesterol-lowering capabilities, could play a role in reducing matrix expansion.
Guijarro
C
C
Department of Medicine, Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis 55415, USA.
Keane
W F
WF
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D003115:Colony-Stimulating Factors / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005921:Glomerulonephritis / Q000517:prevention & control*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D066298:In Vitro Techniques; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use; D008798:Mevalonic Acid / Q000494:pharmacology
D000924:Anticholesteremic Agents; D003115:Colony-Stimulating Factors; D016326:Extracellular Matrix Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003094:Collagen; D008148:Lovastatin; D008798:Mevalonic Acid