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 mn glucose) and 25 mM glucose with 500 mu M 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.