Mechanism of preventive effect of HMG-CoA reductase inhibitor on diabetic nephropathy.
BACKGROUND
Previously, we have found that pravastatin prevents diabetic nephropathy in streptozotocin-induced diabetic rats independently of serum lipid levels. The aim of this study was to clarify the impact of pravastatin on the mesangial cells exposed to high glucose.


METHODS
Rat mesangial cells were cultured in DMEM containing low glucose (5 mM glucose), high glucose (25 mM glucose) and 25 mM glucose with 500 microM pravastatin for 48 hours, respectively. After harvesting, we examined membrane-associated Ras with immunoblot analysis, activity of mitogen-activated protein kinase (MAPK) in the cytosol fraction with in-gel kinase assay and expressions of TGF-beta mRNA with Northern blot analysis.


RESULTS
Membrane-associated Ras, activity of MAP kinase, and expression of transforming growth factor-beta (TGF-beta) mRNA were increased in the mesangial cells cultured exposed to high glucose compared to low glucose. Pravastatin suppressed all these changes in membrane-associated Ras, MAP kinase and TGF-beta mRNA in high glucose.


CONCLUSIONS
This study suggests that pravastatin suppresses the activity of Ras-MAP kinase cascade and induction of TGF-beta in the mesangial cells that have been exposed to high glucose.
Department of Internal Medicine (III), Jikei University School of Medicine, Tokyo, Japan.
T
T
Yokota
K
K
Utsunomiya
Y
Y
Murakawa
H
H
Kurata
N
N
Tajima
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D011905:Genes, ras / Q000235:genetics; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D017035:Pravastatin / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000235:genetics
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D005947:Glucose; D017035:Pravastatin