Lovastatin inhibits transforming growth factor-beta1 expression in diabetic rat glomeruli and cultured rat mesangial cells.
Diabetic nephropathy is a leading cause of end-stage renal disease and is characterized by excessive deposition of extracellular matrix (ECM) proteins in the glomeruli. Transforming growth factor-beta (TGF-beta) is the major mediator of excessive accumulation of ECM proteins in diabetic nephropathy through upregulation of genes encoding ECM proteins as well as downregulation of genes for ECM-degrading enzymes. It has been shown that lovastatin, an inhibitor of 3-hydroxy3-methylglutaryl CoA reductase, delays the onset and progression of different models of experimental nephropathy. To evaluate the effect of lovastatin on the development and progression of diabetic nephropathy, streptozotocin-induced diabetic rats were studied for 12 mo. In untreated diabetic rats, there were significant increases in blood glucose, urine albumin excretion, kidney weight, glomerular volume, and TGF-beta1 mRNA expression in the glomeruli compared with normal control rats treated with citrate buffer only. Treatment with lovastatin in diabetic rats significantly suppressed the increase in urine albumin excretion, kidney weight, glomerular volume, and TGF-beta1 mRNA expression despite high blood glucose levels. To elucidate the mechanisms of the renal effects of lovastatin, rat mesangial cells were cultured under control (5.5 mM) or high (30 mM) glucose with lovastatin alone, mevalonate alone, or with both. Under high glucose, TGF-beta1 and fibronectin mRNA and proteins were upregulated. These high glucose-induced changes were suppressed by lovastatin (10 micro/M) and nearly completely restored by mevalonate (100 microM). These results suggest that lovastatin has a direct cellular effect independent of a cholesterol-lowering effect and delays the onset and progression of diabetic nephropathy, at least in part, through suppression of glomerular expression of TGF-beta1.
Kim
Sung Il
SI
Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea.
Han
Dong Cheol
DC
Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea.
Lee
Hi Bahl
HB
Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea.
D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005353:Fibronectins / Q000187:drug effects / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D005353:Fibronectins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D013311:Streptozocin; D002784:Cholesterol; D008148:Lovastatin; D003404:Creatinine; D008798:Mevalonic Acid